Tag Archive for: myeloproliferative neoplasm treatment
Expert Advice | Living and Thriving With an MPN
Expert Advice | Living and Thriving With an MPN from Patient Empowerment Network on Vimeo.
Is it possible to live well and thrive with a myeloproliferative neoplasm (MPN)? Dr. Naveen Pemmaraju, an MPN specialist and researcher, shares key advice for patients, stressing the importance of taking an active role in learning about their disease and communicating with their team to manage common symptoms and side effects.
Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.
Related Programs:
Transcript:
Katherine Banwell:
In your experience, what does it mean to thrive with an MPN?
Dr. Pemmaraju:
Well, I really love that phrase so much because it’s meaningful to me.
You know, you’re talking about something that resonates with me and my patients, which is not just living with the MPN, but you’re talking about thriving with an MPN. That’s so resonant to us. I think really, I would go for three parts to that.
One is that it’s an acknowledgment or a complete understanding of the disease. So, not denial, the opposite of denial, whatever that is, Katherine. So, understanding as much as you can about the disease which is, I encourage people to Google, look up on the internet. I just, what I want you to do is couple that with talking about it in context with your provider. I think the worry that people have is you’re at your home midnight, you’re Googling stuff, it may or may not be right. So, anyway, so just do that, but then bring the information to the next visit. So, fully understanding and learning as much as you can in your own way. Number two is to be able to have a quality of life that is not just living with the disease, but actually being successful at your relationships, your work, whatever it is that brings you meaning and joy in life. And that sometimes has to do with the MPN paradigm, sometimes has to do with the other stuff we said.
But I think, doing that, not despite the fact that you have the MPN, but acknowledging it with that, right? And then I think the third aspect is, if you have some way or some platform to be able to express yourself with the MPN because it’s such a rare disease, we think maybe only four out of 100,000 people worldwide get these. A lot of patients, not for everybody, by the way, but a lot of patients are thriving on support groups.
It used to be you have to be in person, that’s very difficult to do with rare diseases. But now online, social media, a lot of different ways to get involved. Whether someone’s an introvert or an extrovert, whether someone wants to be private or public, all those things are hugely important, so it’s a personal decision. But for many, they want to get out there, and it’s not necessarily this scientific information exchange, although that’s good. But the support and encouragement and comradery of talking to other patients about what we’re talking about.
It is, in fact, a little bit more facile to do it with the more common diseases, breast cancer, all of these things. And it’s much more difficult, social media online has opened that up. So, to me, I think that’s a kind of mix that I’ve been seeing in my patients. And that leads to empowerment. It leads to taking control of the things that can be controlled, leaving the things that can’t be controlled to what needs to happen. And then an understanding and anticipation of things that may happen in the next few visits, in the next few years. I think that’s how people can thrive with these MPNs.
Katherine Banwell:
Dr. Pemmaraju, When it comes to living and thriving within an MPN, managing disease symptoms and treatment side effects is a big part of that. How can symptoms and side effects impact life with an MPN?
Dr. Pemmaraju:
Katherine, I’m glad you asked about that because I think before we get into the science and the pathobiology and all these complex things, it really starts with the patient. And as you and your team and others have really noted, the MPN for many of our patients, it is a chronic, often lifelong journey. And we really need to reemphasize in this modern era, the patient-centered experience and the caregiver experience.
And so I would emphasize a few things. One is that our MPNs are oftentimes so-called invisible diseases to other people. So, this phrase that just really is tough for us to hear for our patients and our loved ones, “Oh, you don’t look like you’re sick. You don’t look like you have cancer.” So, it emphasizes the internal part of the internal medicine, that’s one.
Number two, it reminds you that you cannot tell on the external what kind of a war, a cytokine war that is going on inside of a patient. And so even though the blood counts are normal, the spleen is okay, the treatment paradigm is going okay, we don’t know what’s really going on. So, that’s why our great friend and colleague Ruben Mesa invented and pioneered the MPN symptom burden to really nail down what’s going on.
And then third is our treatments, Katherine, our treatments, while overall halting or stopping or helping the MPN can then introduce a whole other round of toxicity, side effects, and so we need to manage that.
So, both the disease itself and the treatments, two separate entities, and that’s what we need to be monitoring in the clinic.
Advances in Research | Emerging MPN Therapies on the Horizon
Advances in Research | Emerging MPN Therapies on the Horizon from Patient Empowerment Network on Vimeo.
The pace of research in myeloproliferative neoplasms (MPNs) is advancing rapidly, but what do patients need to know? MPN specialist and researcher Dr. Naveen Pemmaraju shares an update on the latest research and his optimism for the future of MPN care.
Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.
Related Programs:
Transcript:
Katherine Banwell:
Dr. Pemmaraju, as a researcher, what are new and emerging therapies on the horizon in MPN care?
Dr. Pemmaraju:
Well, Katherine, I’m glad you asked because I’m proud to tell you here, at the end of 2023, that we’ve now entered a new golden era of therapies for MPNs. Your group, and others, have led the way in advocating, but for so many years, honestly, we didn’t have many breakthroughs or new medicines. And now we literally have something we’re hearing about once a month. I think this golden era is divided into four buckets, Katherine, and that’s why I’m so excited for our patients and their caregivers. Number one is novel JAK inhibitors. So, beyond the approved ruxolitinib, fedratinib, and now pacritinib, we have a fourth one that’s under consideration, that’s called momelotinib. Hopefully, we’ll have that approved by the end of the year.
[Editor’s Note: Momelotinib (Ojjaara) was approved by the U.S. Food and Drug Administration (FDA) on Sept 15, 2023 for the treatment of intermediate- or high-risk myelofibrosis, in adults with anemia.]
And there are actually other drugs around the world. So, not just in the U.S. and North America that are being developed as a further JAK inhibitor. So, just like we’ve seen in CML with the TKIs for BCR-ABL after the imatinib (Gleevec) medicine, hopefully, we have seven to 10 choices for our patients.
Number two is the combinatorial approach of a JAK inhibitor plus something else. And that’s a field that I’m personally very involved in and helping to lead. The concept there is you take the known workhorse drug, the JAK inhibitor, use it as the backbone, and then add in the second agent. We started to do those studies in patients who were already starting to lose a response and we added in the second agent, those were called suboptimal studies. And then now we’re moving those drugs into the frontline setting in international global randomized studies. So, stay tuned, let’s see how those go.
But the concept is, can you take a new agent, whether it’s a BET inhibitor, a bromodomain inhibitor, a Bcl-xL inhibitor, PI3 Kinase, et cetera, and combine it with the JAK inhibitor? The third bucket that’s even more exciting to many people is that of novel agents standing alone by themselves. Now you’ve had either a JAK inhibitor or some other therapy for your myelofibrosis. That didn’t work for whatever reason. Now you’re looking for a completely new strategy.
An explosion of research, not just in the lab, which we’ve had for the last 10 years, but over the last three or four years, amazingly, even despite the COVID pandemic. I would say dozens, really dozens of trials that are what you would consider beyond or non-JAK inhibitor therapy. Some of them include telomerase inhibition, with the imetelstat agent, for example.
And so the concept here is, can you now hit the myelofibrosis in a completely different pathway? And the answer clearly is yes. And those results have been tested now in the lower stages, the earlier stages, Phase I and II. And you’re starting to see those drugs enter into the phase two and phase three. We eagerly await those results if there can be a viable beyond JAK inhibitor. And then finally, if that wasn’t exciting enough, there’s a fourth bucket, which is thinking about specifically the anemia myelofibrosis. We’ve never really historically done that. We’ve had older drugs, danazol (Danocrine), steroids, growth factor shots, blood transfusions.
But now here you see both pharmaceutical interest, as well as academic interest, in developing agents that either specifically target the anemia of MF or both, the MF and the anemia. And that could be a game changer for our patients in the next five years. So, Katherine, a wealth of exploding research that I’m personally very excited about that gives me and our field hope, momentum, and enthusiasm going into 2024.
Increased MPN Symptoms | What Does It Mean for Patients?
Increased MPN Symptoms | What Does It Mean for Patients? from Patient Empowerment Network on Vimeo.
What might an increase in myeloproliferative neoplasm (MPN) symptoms indicate? MPN specialist Dr. Naveen Pemmaraju discusses possible reasons for an increase in symptoms and shares advice for seeking care when experiencing common issues.
Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.
Related Programs:
Thriving With an MPN | Advice for Setting Goals and Making Treatment Decisions |
Understanding and Managing Common MPN Symptoms and Side Effects |
Transcript:
Katherine Banwell:
What might an increase in symptoms mean? Does it mean that the disease is progressing or that maybe it’s time to change therapies?
Dr. Pemmaraju:
Yeah, possibly. So, with all this objective evidence, there are different buckets of disease progression. And some of them are objective and obvious, rising spleen, increasing blasts, or leukemia cells in the peripheral blood. The start of transfusion dependency for either anemia or platelets that weren’t there before. Sometimes, there are obvious things that you can point to, but there are a couple of scenarios where it’s not as obvious. You just named one. One is increasing symptom burden profile. You see, sometimes you have to think about, is it the sequela of the treatment itself or is it disease progression?
I’ll give an example. If you start on an Interferon product and the dose is too high, you may be feeling not so great from the interferon. But maybe in that case, a simple dose reduction was the answer, because then you’re still getting the anti-disease activity, less side effects and all that. So, I’ll answer your question by saying possibly, but it can’t be the whole story. So, increasing symptoms is a harbinger, it’s a red flag.
In the clinic, it means pause. Workup, is this a subject of the treatment itself? Is it because the disease is progressing? Do we need to do a restaging and workup, whether that means a bone marrow biopsy, whatever that means? Or again, let’s put that other in there. What about the other comorbidities? Do you have class one heart failure, that’s now class three and you’re retaining fluid? And that’s why you’re short of breath and you actually need an echo and a cardiologist and an evaluation of your diuresis. So, I think that’s important, but the key is don’t blow it off, right? So, increasing symptom in MPN is telling you something isn’t right, and we need to check it out.
Katherine Banwell:
Right, and for the patient, tell your healthcare team about it.
Dr. Pemmaraju:
Communicate always. I think what we see is people are so proper and so compassionate and so kind and collegial, and that’s beautiful. But actually in the MPNs and all these rare blood cancers where so little is known and so little is obvious, communication is the key.
Expert Advice | Strategies for Managing MPN-Related Fatigue
Expert Advice | Strategies for Managing MPN-Related Fatigue from Patient Empowerment Network on Vimeo.
Fatigue related to myeloproliferative neoplasms (MPNs) can be overwhelming and may have an impact on other parts of your life. So, what can be done about it? MPN specialist Dr. Naveen Pemmaraju shares advice for understanding and managing this common symptom, including lifestyle choices that may be beneficial.
Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.
Related Programs:
Transcript:
Katherine Banwell:
Well, it’s obvious that there’s some symptom overlap along with this. And so I’m wondering what the strategies are for managing these. Let’s start with fatigue first.
Dr. Pemmaraju:
Let’s do that.
Katherine Banwell:
How do you manage that?
Dr. Pemmaraju:
This is one of the tougher parts of what we do. I’m glad you’re pinning me down to say it, because really this is the majority of what we need to be talking about in the clinic. I’m going to just be honest, you know, with all the scientific breakthroughs and everything, some of these are limited. The fatigue, this is some of the strategies I use and some of the experts in the field. I think one is managing the underlying disease. So, as you mentioned, if you have high-risk, intermediate to high-risk myelofibrosis, one of the great findings of our field is the JAK inhibitor class generally helps to improve symptom burden.
So, that is the splenomegaly, the fatigue, the pruritus. Maybe not so much the itching, but some of these other things. So, I think treating the underlying disease, that’s okay. Number two is many clinics, onc centers around the country are starting to open up a supportive care or fatigue center clinic. So, I am referring several of my patients there, we’re talking about diet, nutrition, exercise. We used to never talk about these things. Ruben Mesa has found that doing yoga and meditation can genuinely actually help the pathobiology to reduce the cytokine storm and improve the fatigue and quality of life.
Dr. Angela Fleischman, our colleague at UC Irvine, has done work suggesting that possibly an antioxidant diet such as the Mediterranean diet can help the overall general fatigue, well-being, wellness. And then of course I mentioned earlier, but I’ll mention here too, sometimes fatigue is outside of the MPN. Have you had your TSH or thyroid checked? What about your vitamin D levels? How are you doing on these PCP general checks? Things that may be contributing to the life and the happiness.
And finally, let me make a plug for mental health. I don’t know how much we were emphasizing before the COVID pandemic, but after, the last three or four years have been tough. Healthcare providers, caregivers, patients themselves, mental health checkup, that can also be contributing to fatigue, not getting out of bed, in addition to the organic medical problems. So, let me advocate a multifactorial approach, scientifically summed up as treating what you can with the underlying MPN, fine, treating the side effects and symptoms of the MPN, as you said.
And then, other, which can be a huge bucket, particularly as we get older, to not forget about that. Again, checking the thyroid level. And then when you’re on these different treatments, you can personalize it. Interferon, obviously, has its own separate set of side effects and then of course the other agents. So, I think that may be the best way to approach it. Maybe a three-bucket approach. The MPN itself, and then the treatment itself, and then the other, something like that.
Katherine Banwell:
And as you’ve mentioned, it’s all going to be personalized and individualized.
Dr. Pemmaraju:
Hugely.
Katherine Banwell:
Right, because what’s going to work for one person is not necessarily going to work for another.
Dr. Pemmaraju:
Hear, hear, well said to that. You know, you think you make a great diagnosis in the clinic, someone’s having fatigue, they’re on therapy for your MPN. You check the TSH, it’s wildly abnormal. Okay, you refer them to endocrine. Six months later, the thyroid level is completely normal now on thyroid medicine. And yet, the fatigue, brain fog, everything is still not clear.
The MPN is under good control. What gives? That’s the difficult part of these diseases. So, I really love what you said about the personalization and to keep looking and keep trying.
Common MPN Treatment Side Effects | Strategies for Management
Common MPN Treatment Side Effects | Strategies for Management from Patient Empowerment Network on Vimeo.
When starting treatment for myelofibrosis (MF), polycythemia vera (PV), or essential thrombocythemia (ET), what side effects might one expect? MPN specialist Dr. Naveen Pemmaraju provides an overview of MPN treatments, common issues patients may experience, and strategies for managing these side effects.
Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.
Related Programs:
Common MPN Symptoms: What Are They and How Are They Managed? |
Transcript:
Katherine Banwell:
What are the most common issues associated with the main MPN treatment classes? Let’s start with JAK inhibitors.
Dr. Pemmaraju:
Oh, very nice. Yeah, that’s exactly the way I think about it too. So, with our JAK inhibitors, we now have 10 years since the approval of the ruxolitinib (Jakafi), the first in class. And now we have two more approved agents which are known as fedratinib (Inrebic) and pacritinib (Vonjo), and hopefully a fourth agent, momelotinib (Ojjaara), which is under regulatory review at this time.
[Editor’s Note: Momelotinib (Ojjaara) was approved by the U.S. Food and Drug Administration (FDA) on Sept 15, 2023 for the treatment of intermediate- or high-risk myelofibrosis, in adults with anemia.]
So, we have a whole class of drugs. They have some similarities and then some differences, but in general, the JAK inhibitor class are well-tolerated drugs, but each of them has some side effects.
I’d like to go through them just as a top-line overview. It’s very important. Number one for the ruxolitinib agent, the one that’s been around longest. This one is usually well-tolerated as we said, but you do have to look out for a few things. Non-melanoma skin cancers can be increased in some of our patients, so the importance of dermatology and skin evaluations. Some infections such as viral herpes, zoster, and shingles, so we need to be aware of that. And then weight gain, weight gain is something that we’re seeing more over time as we appreciate the drug, particularly as we move it into earlier lines of therapy, such as p. vera.
As I look at the other agents, the fedratinib already carries an FDA black box warning for an encephalopathy syndrome, thought to be Wernicke’s encephalopathy, which can affect the brain. But really an encephalopathy syndrome, which means we have to check thiamine levels and replace them and be aware of that. That’s vitamin B1 and also GI side effects with that agent. And then finally, the pacritinib agent has a few toxicity and side effects.
Again, all these are on the package label insert, well-known. Some GI side effects, particularly in the first few months, including diarrhea, and we need to watch out for bleeding and these kinds of effects, especially in the opening days and weeks of the agent. So, again, JAK inhibitors, well-tolerated class, oral medicines, but can have some notable side effects that we have to follow together in the clinic.
Katherine Banwell:
What about interferon? What are some common side effects?
Dr. Pemmaraju:
Yeah, great. So, the interferon class, which actually now is a class of drugs. We started out as let’s call it the regular interferon, which was multiple times a week dosing. Then the pegylated interferon, which went down to once a week. And then now we have the ropeginterferon (Besremi), which is the recently approved agent in p. vera, which is every two weeks spaced out to every month.
So, as you said, in this class of drugs, what’s old is new again. These drugs have actually been around longer than the JAK inhibitors, interestingly. You do have to be mindful. These are a very serious set of drugs. We usually set aside a good amount of time to talk about the side effects, and they are many historically.
The main ones include psychiatric neurological side effects. So, it can cause a depressed mood, change in the mood, even depression. Hugely important, so everyone needs to be aware of that, including the caregivers. It can cause autoimmune side effects, so such as thyroid, liver, these type of side effects. And then finally, of course, any of these interferons can cause a flu-like profile, you know, not feeling well, particularly in the beginning days. So, we usually try to mitigate it with lots of education to the patient, the caregiver, remind all members of the team.
If you can, maybe even start at a low dose and escalate up, which is what we’re trying to do in the clinic. And then really close monitoring for stuff that you can monitor, the thyroid, the liver, the mental side effects, as we said. Usually most of our patients over time, most of them do get used to the drug. So, there is some kind of an immune component to it, but you can have side effects at any time.
I would say also, Katherine, that these later forms of the interferon continue to improve. And so we’re seeing either less and less side effects or at least better managed, better tolerated, more understanding of these. So, a great class of drugs. And I should also say that our colleagues around the world are starting to combine the two classes of drugs for patients with myelofibrosis. And so we need to be paying attention to those combinatorial approaches.
Katherine Banwell:
What about Hydrea (hydroxyurea)?
Dr. Pemmaraju:
Yeah, so hydroxyurea, we also have to mention that.
One of the workhorse medicines of our field. We use it in all the MPNs.
Again, an older class of drugs such as the Interferons that have been around prior to the JAK inhibitors. Used in a variety of diseases, both benign and malignant, used in sickle cell anemia. Historically has been used in both blood and solid tumor cancers, but we use it very commonly in MPNs. Almost all of our viewers are familiar. Hydroxyurea is not a benign drug. It is a chemotherapeutic agent. You know, you have to handle it with care.
And so it’s got a few side effects. It can cause some fatigue in some patients. One of the more notable classical side effects is an ulcer formation, either in the mouth area or in the lower extremities, such is in the feet, so, you know, grossly visible. It can cause some fever and not feeling well in some patients. I will say again, a lot of these drugs are generally well-tolerated. Most of our patients are 60, 70, 80, and older, but you can certainly have those side effects. A lot of these drugs, Katherine, can affect the skin.
I did mention that earlier. So, ruxolitinib, even the interferons, hydrea, they can all cause skin lesions, maybe some of them associated with non-melanoma skin cancer, such as squamous cell and basal cell. So, one amazing part of the practice has been close association with our dermatology colleagues, not something I would have expected 10, 15 years ago. And that’s been a helpful part of the practice.
So, I think it’s a point where I can emphasize that, in addition to having us as the MPN or blood cancer team, Katherine, the pandemic has reminded us the importance of primary care team as well. So, it’s really two teams, someone checking the cholesterol, cancer screenings, skin checkups, mammogram, PSAs. And then in coordination with your MPN team and then everyone working together, so colonoscopies, et cetera. So, just a plug there, especially the last three, four years where people have gotten behind to make sure that we’re keeping up with that part of the deal as well.
Katherine Banwell:
With all the testing, yeah.
Dr. Pemmaraju:
Exactly, right.
Katherine Banwell:
You mentioned a couple of treatment side effects and how they’re managed, but in general, across the board, are treatment side effects managed in the same way, in similar ways?
Dr. Pemmaraju:
Now, that’s a great question. So, here I’ve given you this nice list, kind of academic version of the list, but boy, no, right. And all my patients and everyone out there knows that there’s some varied practices. You know, the varied practices are not only, as you say, across the country and across the world, but also even in our own clinics, patient to patient. The MPNs have humbled and taught us that one person’s MPN can be starkly different from the next, so on and so forth. So, I’m not just talking about the difference between PV, ET, myelofibrosis, and systemic mastocytosis. I’m talking about one person’s MF is completely different than the other. I think there are a couple of things I didn’t mention. So, pruritus, or itching is one of the great symptoms really. It’s not a side effect usually, but it’s a symptom of the MPN. There are some ways to treat that in the clinic.
Fatigue really has no great way to treat it. Usually when you introduce one of the JAK inhibitors that can improve. On the side effects side, as we were mentioning, a lot of these are unsatisfying things. The flu-like symptoms of the interferon, the weight gain of the JAK inhibitor. So, I think what you’re saying is so correct, and let me admit it, I’m going to be the first to admit it, there’s not really a good standard playbook.
But on the other hand, I think personalization. As we’ve always said, in our rare disease space, if you have a disease, it’s not rare to you. It’s what you have, it’s what your spouse is dealing with, your loved one, your mother with you. And so, I would advocate here that there’s a personalized playbook there. I would say that there are three guiding principles though. One is when you have side effects of a medicine, the first thing to do is let your healthcare provider team know. I know that sounds obvious, but here I am in the clinic and sometimes we don’t find out until later. And so some of that is because the patient says to themselves, let’s tough it out. Or they may not know, or they may not be able to, or it may not be easy to communicate with our healthcare teams.
Two is when you’re evaluating, every patient’s case is different. This is not specific advice, as you said, at the top of the hour here. But in a general sense, you really need to evaluate if the side effect is peculiar or particular to just that patient case, so idiosyncratic, unpredictable, notable.
Or, is it a general expected sort of something that you thought could already happen and then go with it from there? And then finally, the concept of dose interruptions, dose reductions, treatment holidays, something very important. So, basically a lot of different ways you can go, but no standard or uniform playbook in our MPN field, as you and the team well knows.
PODCAST: Thriving With an MPN | Managing Symptoms and Treatment Side Effects
In this podcast, MPN specialist Dr. Naveen Pemmaraju, discusses strategies for managing symptoms and treatment side effects for people living with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Dr. Pemmaraju also shares advice for communicating with your healthcare team and provides an update on the latest MPN treatment and research.
Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.
Transcript:
Katherine Banwell:
Hello and welcome. I’m your host, Katherine Banwell. Today’s program is a continuation of our Thrive Series and we’re going to discuss coping with MPN symptoms and managing treatment side effects. Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you.
Let’s meet our guest today. Joining me is Dr. Naveen Pemmaraju. Dr. Pemmaraju, welcome. Would you please introduce yourself?
Dr. Pemmaraju:
Oh, thank you, Katherine and team. Just an honor to be here.
I’m Naveen Pemmaraju, a professor of leukemia at MD Anderson Cancer Center in Houston. And I also serve as one of our executive directors for the MD Anderson Cancer Network, and I specialize in MPNs and rare leukemia. So, happy to join you once again, Katherine.
Katherine Banwell:
Thank you so much for being with us today, taking time out of your schedule. Well, Dr. Pemmaraju, when it comes to living and thriving within an MPN, managing disease symptoms and treatment side effects is a big part of that. How can symptoms and side effects impact life with an MPN?
Dr. Pemmaraju:
Katherine, I’m glad you asked about that because I think before we get into the science and the pathobiology and all these complex things, it really starts with the patient. And as you and your team and others have really noted, the MPN for many of our patients, it is a chronic, often lifelong journey. And we really need to reemphasize in this modern era, the patient-centered experience and the caregiver experience.
And so I would emphasize a few things. One is that our MPNs are oftentimes so-called invisible diseases to other people. So, this phrase that just really is tough for us to hear for our patients and our loved ones, oh, you don’t look that you’re sick. You don’t look like you have cancer. So, it emphasizes the internal part of the internal medicine, that’s one. Number two, it reminds you that you cannot tell on the external what kind of a war, a cytokine war that is going on inside of a patient. And so even though the blood counts are normal, the spleen is okay, the treatment paradigm is going okay, we don’t know what’s really going on. So, that’s why our great friend and colleague Ruben Mesa invented and pioneered the MPN symptom burden to really nail down what’s going on.
And then third is our treatments, Katherine, our treatments, while overall halting or stopping or helping the MPN can then introduce a whole other round of toxicity, side effects, and so we need to manage that.
So, both the disease itself and the treatments, two separate entities, and that’s what we need to be monitoring in the clinic.
Katherine Banwell:
All right, well, thank you for that. As we get into the discussion, Dr. Pemmaraju, it’s important to note that some of the issues we’ll be talking about today are symptoms of the MPN, and others may be treatment-related side effects. So, let’s start with side effects. What are the most common issues associated with the main MPN treatment classes? Let’s start with JAK inhibitors.
Dr. Pemmaraju:
Oh, very nice. Yeah, that’s exactly the way I think about it too. So, with our JAK inhibitors, we now have 10 years since the approval of the ruxolitinib, the first in class. And now we have two more approved agents which are known as fedratinib (Inrebic) and pacritinib (Vonjo), and hopefully a fourth agent, momelotinib, which is under regulatory review at this time.
So, we have a whole class of drugs. They have some similarities and then some differences, but in general, the JAK inhibitor class are well-tolerated drugs, but each of them has some side effects.
I’d like to go through them just as a top-line overview. It’s very important. Number one for the ruxolitinib agent, the one that’s been around longest. This one is usually well-tolerated as we said, but you do have to look out for a few things. Non-melanoma skin cancers can be increased in some of our patients, so the importance of dermatology and skin evaluations. Some infections such as viral herpes, zoster, and shingles, so we need to be aware of that. And then weight gain, weight gain is something that we’re seeing more over time as we appreciate the drug, particularly as we move it into earlier lines of therapy, such as p.- vera.
As I look at the other agents, the fedratinib already carries an FDA black box warning for an encephalopathy syndrome, thought to be Wernicke’s encephalopathy, which can affect the brain. But really an encephalopathy syndrome, which means we have to check thiamine levels and replace them and be aware of that. That’s vitamin B1 and also GI side effects with that agent. And then finally, the pacritinib agent has a few toxicity and side effects.
Again, all these are on the package label insert, well-known. Some GI side effects, particularly in the first few months, including diarrhea, and we need to watch out for bleeding and these kinds of effects, especially in the opening days and weeks of the agent. So, again, JAK inhibitors, well-tolerated class, oral medicines, but can have some notable side effects that we have to follow together in the clinic.
Katherine Banwell:
What about interferon? What are some common side effects?
Dr. Pemmaraju:
Yeah, great. So, the interferon class, which actually now is a class of drugs. We started out as let’s call it the regular Interferon, which was multiple times a week dosing. Then the Pegylated Interferon, which went down to once a week. And then now we have the ropeginterferon (Besremi), which is the recently approved agent in p. vera, which is every two weeks spaced out to every month.
So, as you said, in this class of drugs, what’s old is new again. These drugs have actually been around longer than the JAK inhibitors, interestingly. You do have to be mindful. These are a very serious set of drugs. We usually set aside a good amount of time to talk about the side effects, and they are many historically.
The main ones include psychiatric neurological side effects. So, it can cause a depressed mood, change in the mood, even depression. Hugely important, so everyone needs to be aware of that, including the caregivers. It can cause autoimmune side effects, so such as thyroid, liver, these type of side effects. And then finally, of course, any of these Interferons can cause a flu-like profile, you know, not feeling well, particularly in the beginning days.
So, we usually try to mitigate it with lots of education to the patient, the caregiver, remind all members of the team. If you can, maybe even start at a low dose and escalate up, which is what we’re trying to do in the clinic. And then really close monitoring for stuff that you can monitor, the thyroid, the liver, the mental side effects, as we said. Usually most of our patients over time, most of them do get used to the drug. So, there is some kind of an immune component to it, but you can have side effects at any time.
I would say also, Katherine, that these later forms of the Interferon continue to improve. And so we’re seeing either less and less side effects or at least better managed, better tolerated, more understanding of these. So, a great class of drugs. And I should also say that our colleagues around the world are starting to combine the two classes of drugs for patients with myelofibrosis. And so we need to be paying attention to those combinatorial approaches.
Katherine Banwell:
What about hydrea?
Dr. Pemmaraju:
Yeah, right. Yeah, so hydroxyurea, we also have to mention that.
One of the workhorse medicines of our field. We use it in all the MPNs.
Again, an older class of drugs such as the Interferons that have been around prior to the JAK inhibitors. Used in a variety of diseases, both benign and malignant, used in sickle cell anemia. Historically has been used in both blood and solid tumor cancers, but we use it very commonly in MPNs. Almost all of our viewers are familiar. Hydroxyurea is not a benign drug. It is a chemotherapeutic agent. You know, you have to handle it with care.
And so it’s got a few side effects. It can cause some fatigue in some patients. One of the more notable classical side effects is an ulcer formation, either in the mouth area or in the lower extremities, such is in the feet, so, you know, grossly visible. It can cause some fever and not feeling well in some patients. I will say again, a lot of these drugs are generally well tolerated. Most of our patients are 60, 70, 80, and older, but you can certainly have those side effects. A lot of these drugs, Katherine, can affect the skin.
I did mention that earlier. So, ruxolitinib, even the interferons, hydrea, they can all cause skin lesions, maybe some of them associated with non-melanoma skin cancer, such as squamous cell and basal cell. So, one amazing part of the practice has been close association with our dermatology colleagues, not something I would have expected 10, 15 years ago. And that’s been a helpful part of the practice.
So, I think it’s a point where I can emphasize that, in addition to having us as the MPN or blood cancer team, Katherine, the pandemic has reminded us the importance of primary care team as well. So, it’s really two teams, someone checking the cholesterol, cancer screenings, skin checkups, mammogram, PSAs. And then in coordination with your MPN team and then everyone working together, so colonoscopies, et cetera. So, just a plug there, especially the last three, four years where people have gotten behind to make sure that we’re keeping up with that part of the deal as well.
Katherine Banwell:
With all the testing, yeah.
Dr. Pemmaraju:
Exactly, right.
Katherine Banwell:
You mentioned a couple of treatment side effects and how they’re managed, but in general, across the board, are treatment side effects managed in the same way, in similar ways?
Dr. Pemmaraju:
Now, that’s a great question. So, here I’ve given you this nice list, kind of academic version of the list, but boy, no, right. And all my patients and everyone out there knows that there’s some varied practices. You know, the varied practices are not only, as you say, across the country and across the world, but also even in our own clinics, patient to patient. The MPNs have humbled and taught us that one person’s MPN can be starkly different from the next, so on and so forth.
So, I’m not just talking about the difference between PV, ET, myelofibrosis, and systemic mastocytosis. I’m talking about one person’s MF is completely different than the other. I think there are a couple of things I didn’t mention. So, pruritus, or itching is one of the great symptoms really. It’s not a side effect usually, but it’s a symptom of the MPN. There are some ways to treat that in the clinic.
Fatigue really has no great way to treat it. Usually when you introduce one of the JAK inhibitors that can improve. On the side effects side, as we were mentioning, a lot of these are unsatisfying things. The flu-like symptoms of the interferon, the weight gain of the JAK inhibitor. So, I think what you’re saying is so correct, and let me admit it, I’m going to be the first to admit it, there’s not really a good standard playbook.
But on the other hand, I think personalization. As we’ve always said, in our rare disease space, if you have a disease, it’s not rare to you. It’s what you have, it’s what your spouse is dealing with, your loved one, your mother with you. And so, I would advocate here that there’s a personalized playbook there. I would say that there are three guiding principles though. One is when you have side effects of a medicine, the first thing to do is let your healthcare provider team know. I know that sounds obvious, but here I am in the clinic and sometimes we don’t find out until later.
And so some of that is because the patient says to themselves, let’s tough it out. Or they may not know, or they may not be able to, or it may not be easy to communicate with our healthcare teams. Two is when you’re evaluating, every patient’s case is different. This is not specific advice, as you said, at the top of the hour here. But in a general sense, you really need to evaluate if the side effect is peculiar or particular to just that patient case, so idiosyncratic, unpredictable, notable.
Or, is it a general expected sort of something that you thought could already happen and then go with it from there? And then finally, the concept of dose interruptions, dose reductions, treatment holidays, something very important. So, basically a lot of different ways you can go, but no standard or uniform playbook in our MPN field, as you and the team well knows.
Katherine Banwell:
Thank you for that Dr. Pemmaraju. I’d like to move on to common MPN symptoms now. Let’s start with myelofibrosis. What are the symptoms associated with this particular MPN?
Dr. Pemmaraju:
Excellent question. So, for the myelofibrosis, generally thought to be our most advanced of the MPNs, can be low risk, intermediate to high risk. We’ll focus our comments here on intermediate to high risk, the more advanced MF. This is important because not only what I’m going to tell you is sort of a subjective list of symptoms, but because of the work of my great friend, Ruben Mesa, who pioneered the MPN symptom burden, we’ve actually been able to, as he and I say, quantify the unquantifiable.
So, take subjective information and turn it into objective. For example, we know that among the three MPNs, PV, ET, and MF, that fatigue is by far the most common symptom that our patients report. It’s a fatigue that’s more than the general feeling tired at the end of the day. It’s sometimes a wiped-out fatigue. Some of our patients will have pruritus or itching. Many of our patients will have early satiety, which means getting full too early because either the spleen is too big, decreasing the appetite. Bone pain and neuropathy can happen in our MF patients. Brain fog and decreased concentration, huge issue among a lot of our patients.
And finally, because of the low blood counts, if a myelofibrosis patient is anemic, they can have those issues. So, fatigue, shortness of breath, even chest pain and palpitations. If the platelets are too low, or too high for that matter, bleeding or clotting.
So, the problem with myelofibrosis, it ranges the gamut from the low-risk patients, who can be treated maybe even as a PV or ET observation or not as advanced treatment paradigm, all the way to intermediate high risk where patients are cachectic, losing weight, not feeling well, drenching night sweats. And all of these can be captured on not only the scoring systems but also the symptom burden scales. And to be honest with you, this is the majority of what our patients are feeling outside of the blood counts and outside of the objective information. So much so to the point, Katherine, where a patient can present with these symptoms solely, without ever having a blood count or a bone marrow or anything, and then it leads to the work of it.
Katherine Banwell:
Oh, wow. Wow, fascinating. What about symptoms for polycythemia vera?
Dr. Pemmaraju:
Yeah, so this is a great theme that you’ve got going here, which is know your body. If you know your body, then you’re able to tell what’s abnormal or normal. p. vera can be a bit more subtle.
Oftentimes patients with p. vera can have a normal life expectancy and the longer term series in Europe show that it’s basically about the same life expectancy as the general population or slightly lower. But that doesn’t tell the whole story. Patients with p. vera can have an unbelievable symptom burden, either from the hyperviscosity of the hematocrit, the blood level being too high or the cytokine storm, that I mentioned, that makes people feel not well. So fatigue, brain fog, feelings of sluggishness, feeling too full, those are common in p. vera.
The treatments are aimed at trying to make that better. So, phlebotomy to bring the hematocrit down below 45 can make you feel a little bit lighter, a little bit better, decrease the brain fog. If you’re using either the standard treatments of hydrea or Interferon, and then, of course, the baby aspirin to prevent clots, heart attacks, stroke. The newer agents in p. vera include the ropeginterferon that we mentioned earlier, clinical trials, such as the PTG-300 that I’m a part of, that try to really keep the blood levels normal all the time.
And so hopefully help to improve the quality of life, decrease the chance of having a clot, and also hopefully try to make patients feel better from these aspects.
Katherine Banwell:
What about essential thrombocythemia or ET?
Dr. Pemmaraju:
ET, again, just like PV, you can have a lot of patients who are either incidentally diagnosed or not too much of a symptom burden. But again, here, the blood counts don’t tell the story. You can have “low risk ET” which is defined as less than 60 or no prior blood clots. So, you can be 43 years old, diagnosed with ET, your blood counts aren’t that high, but yet you’re still feeling overwhelming fatigue, itching. You’re seeing flashing things in your eyes called scotomas. You’re having small nerve or vascular issues called erythromelalgias. It’s a very elusive and difficult disease, particularly for our young patients. So, in ET, again, the same set of symptoms can happen. This fatigue, itching, the brain fog, concentration, bleeding, and or clotting.
And so again, the goal of therapy is to mitigate those. If you’re young, a lot of patients are either observed or baby aspirin. If you’re older than 60 or have high risk features, then again, cytoreductive therapy. The other aspect I should mention is you can start out with one of these and it transforms into the other. That’s called clinical or phenotypic shifts. You can start out as an ET, go to PV. You can start out as PV and go to myelofibrosis. You can start out as myelofibrosis and go to acute myeloid leukemia. So, that’s why follow-up, even over years, decades, is important, preferably with an expert team, because you never know when one of these things wants to transform. And then your side effect, or I should say your symptom profile therefore changes with that transformation.
Katherine Banwell:
Well, it’s obvious that there’s some symptom overlap along with this.
Dr. Pemmaraju:
Right.
Katherine Banwell:
And so I’m wondering what the strategies are for managing these. Let’s start with fatigue first.
Dr. Pemmaraju:
Let’s do that.
Katherine Banwell:
How do you manage that?
Dr. Pemmaraju:
This is one of the tougher parts of what we do. I’m glad you’re pinning me down to say it because really this is the majority of what we need to be talking about in the clinic. I’m going to just be honest, you know, with all the scientific breakthroughs and everything, some of these are limited. The fatigue, this is some of the strategies I use and some of the experts in the field. I think one is managing the underlying disease. So, as you mentioned, if you have high-risk, intermediate to high-risk myelofibrosis, one of the great findings of our field is the JAK inhibitor class generally helps to improve symptom burden.
So, that is the splenomegaly, the fatigue, the pruritus. Maybe not so much the itching, but some of these other things. So, I think treating the underlying disease, that’s okay. Number two is many clinics, Onc centers around the country are starting to open up a supportive care or fatigue center clinic. So, I am referring several of my patients there, we’re talking about diet, nutrition, exercise. We used to never talk about these things. Ruben Mesa has found that doing yoga and meditation can genuinely actually help the pathobiology to reduce the cytokine storm and improve the fatigue and quality of life.
Dr. Angela Fleischman, our colleague at UC Irvine, has done work suggesting that possibly an antioxidant diet such as the Mediterranean diet can help the overall general fatigue, well-being, wellness. And then of course I mentioned earlier, but I’ll mention here too, sometimes fatigue is outside of the MPN. Have you had your TSH or thyroid checked? What about your vitamin D levels? How are you doing on these PCP general checks? Things that may be contributing to the life and the happiness.
And finally, let me make a plug for mental health. I don’t know how much we were emphasizing before the COVID pandemic, but after, the last three or four years have been tough. Healthcare providers, caregivers, patients themselves, mental health checkup, that can also be contributing to fatigue, not getting out of bed, in addition to the organic medical problems. So, let me advocate a multifactorial approach, scientifically summed up as treating what you can with the underlying MPN, fine, treating the side effects and symptoms of the MPN, as you said.
And then, other, which can be a huge bucket, particularly as we get older, to not forget about that. Again, checking the thyroid level. And then when you’re on these different treatments, you can personalize it. Interferon, obviously, has its own separate set of side effects and then of course the other agents. So, I think that may be the best way to approach it. Maybe a three-bucket approach. The MPN itself, and then the treatment itself, and then the other, something like that.
Katherine Banwell:
Yeah, yeah. And as you’ve mentioned, it’s all going to be personalized and individualized, because what’s going to work for one person is not necessarily going to work for another.
Dr. Pemmaraju:
Hear, hear, well said to that. You know, you think you make a great diagnosis in the clinic, someone’s having fatigue, they’re on therapy for your MPN. You check the TSH, it’s wildly abnormal. Okay, you refer them to endocrine. Six months later, the thyroid level is completely normal now on thyroid medicine. And yet, the fatigue, brain fog, everything is still not clear.
The MPN is under good control. What gives? That’s the difficult part of these diseases. So, I really love what you said about the personalization and to keep looking and keep trying.
Katherine Banwell:
What might an increase in symptoms mean? Does it mean that the disease is progressing or that maybe it’s time to change therapies?
Dr. Pemmaraju:
Yeah, possibly. So, with all this objective evidence, there’s different buckets of disease progression. And some of them are objective and obvious, rising spleen, increasing blasts, or leukemia cells in the peripheral blood. The start of transfusion dependency for either anemia or platelets that weren’t there before. Sometimes, there are obvious things that you can point to, but there are a couple of scenarios where it’s not as obvious. You just named one. One is increasing symptom burden profile. You see, sometimes you have to think about, is it the sequela of the treatment itself or is it disease progression?
I’ll give an example. If you start on an Interferon product and the dose is too high, you may be feeling not so great from the Interferon. But maybe in that case, a simple dose reduction was the answer because then you’re still getting the anti-disease activity, less side effects and all that. So, I’ll answer your question by saying possibly, but it can’t be the whole story. So, increasing symptoms is a harbinger, it’s a red flag. In the clinic, it means pause. Workup, is this a subject of the treatment itself? Is it because the disease is progressing? Do we need to do a restaging and workup, whether that means a bone marrow biopsy, whatever that means?
Or again, let’s put that other in there. What about the other comorbidities? Do you have class one heart failure, that’s now class three and you’re retaining fluid? And that’s why you’re short of breath and you actually need an echo and a cardiologist and an evaluation of your diuresis. So, I think that’s important, but the key is don’t blow it off, right? So, increasing symptom in MPN is telling you something isn’t right, and we need to check it out.
Katherine Banwell:
Right, and for the patient, tell your healthcare team about it.
Dr. Pemmaraju:
Communicate always. I think what we see is people are so proper and so compassionate and so kind and collegial, and that’s beautiful. But actually in the MPNs and all these rare blood cancers where so little is known and so little is obvious, communication is the key.
Katherine Banwell:
Yeah. I’d like to make some time now to answer questions from the audience.
Dr. Pemmaraju:
Great.
Katherine Banwell:
And here are a few we received prior to the program. Stephanie writes, I have ET and I’m not being treated. Do you have advice for the watch and wait period? I’m anxious about the disease changing and don’t know what I’m waiting for. So, before you answer the question, Dr. Pemmaraju, would you define this term, watch and wait?
Dr. Pemmaraju:
I will. And to Stephanie and everyone out there, this is a great question. I will say half the folks I talk to actually call it watch and worry, okay. Some people call it watch and wait, and as Stephanie’s saying, some people call it watch and worry.
Yeah, the concept is threefold. One is that there are many cancers, many cancers, including blood cancers, that can be caught so early on that they don’t require treatment. A lot of patients with CLL, chronic lymphocytic leukemia, ET, as Stephanie mentioned, in the solid tumor. It’s very common to be diagnosed with a prostate cancer that’s low grade, early stage that can be observed. Number two is in ET, there is a science behind it.
What we found in our studies, and they can be updated over time and you’ll see those, the traditional is that if you’re below the age of 60 and/or you’ve had no blood clot, thrombotic event, that’s considered low risk. And the treatment can be observation, perhaps adding in a baby aspirin to prevent against blood clots if there’s no contraindication. Now what’s magic about that age 60, obviously as you know, it’s not magic. It’s more of a statistical, continuous variable algorithm that says around that time, the risk of blood clots goes up. And so then you’d consider cytoreductive therapy at that point. Now there’s exceptions to that.
Many of our young patients are on therapy, but there’s usually some reason for that. Some high-risk feature, wildly uncontrolled blood counts, for example, symptom burden, some other high-risk features. So, it’s a suggestion. It’s a guideline, not an absolute. And then the third part of it is, the what do you do in that time? And that’s the frustrating thing. And I think that’s what Stephanie’s getting to.
Again, that’s why I said the watch and worry versus watch and wait. Some of it is, how are you feeling outside of this? Some patients take it as a great news. Hey, you have this blood cancer, that’s not good news. But the good news is it’s probably not going to be active for a long time, we can, “just watch it.” But some people, as Stephanie is saying, take it the opposite way. What do you mean I got a blood cancer? I got something lurking in my body. You’re telling me it’s there, you know it’s there. And so what’s up with that? And the concept there is that some of these situations like low-risk ET, we found that if you treat too early, too aggressively, you can actually do harm.
Katherine Banwell:
Oh.
Dr. Pemmaraju:
So, that’s the key. These chemo drugs are not benign as you had me discuss earlier. They have toxicity, side effects, short-term, long-term. So, it’s a risk-benefit thing. If the risk far outweighs the benefit, as in the younger patient with no symptoms, no high-risk features, observation is okay. But at some point, when it turns, that’s the threshold.
So, really the key is, if we believe these are stem cell blood cancer disorders, we need to be thinking about and designing therapies with minimal to no toxicity. Something that actually modifies the disease early on and something that leads to long-term outcomes. And we don’t have that yet in ET. We’re working on that in PV and myelofibrosis. So, stay tuned for that. And then finally, let me also add, this is an important point, not everybody gets it. This watch and wait versus watch and worry. So, I’m glad Stephanie brought that up because it’s not always good news, uniformly, when you tell someone, good news is you don’t have to do anything bad news, there’s something there.
Katherine Banwell:
Right. Jess wrote in with this question. I’ve been experiencing bone pain and neuropathy. Is there anything that can eliminate or reduce these symptoms?
Dr. Pemmaraju:
Great question, and it ties into our earlier question about the MPN symptom burden. On the original MPN-10 scale that Ruben and others pioneered, you will see both of those. You will see the bone pain, neuropathy.
Now there’s been, you know, different narrowing down of these questionnaires and things, but in general, our patients do have these and that’s across the board. So, not only myelofibrosis but also our patients with PV and ET. These are among the most frustrating, I would say. Again, as you would expect, if you are advanced enough and you’re getting treatment, you hope that the treatment itself, whether it’s the Interferon or the JAK inhibitors or whatever you’re doing, clinical trial, hopes to alleviate those. But it doesn’t all the time.
Then the second issue is, these are likely the result of a cytokine storm or increased cytokines, these protein messengers that are abnormally high in our patients with MPNs. There’s varying unsatisfying things that people do. Sometimes we give antihistamines for people with bone pain. So that’s these over-the-counter sinus allergy medicines. Interestingly, the Claritins and the Zyrtecs, these type of medications, that can sometimes help in MPN bone pain. And then also for the neuropathy, these common neuropathy drugs that everybody knows, the gabapentins and all of these drugs are used frequently.
There’s no doubt in my clinic and everybody else’s, but the varying levels of success. So, I think it speaks to the fact that these two are kind of from the MPN itself. And treating the underlying MPN is still usually your best strategy, using these, borrowing these medications, from the other aspects.
And then finally, my other plug here, which has kind of been a theme here, hopefully it resonates, and it doesn’t sound generic or unnecessary, is these things can sometimes be something else. Okay, bone pain and neuropathy can be something else. So, we do have cases of people having frequent falls, really serious stuff. In those cases, I refer those patients to a neurologist. Nerve conduction studies right, very advanced studies in the couple of cases that are so severe that it’s beyond thinking that it’s just due to the MPN.
Katherine Banwell:
Dr. Pemmaraju, as a researcher, what are new and emerging therapies on the horizon in MPN care?
Dr. Pemmaraju:
Well, Katherine, I’m glad you asked because I’m proud to tell you here, at the end of 2023, that we’ve now entered a new golden era of therapies for MPNs. Your group, and others, have led the way in advocating, but for so many years, honestly, we didn’t have many breakthroughs or new medicines. And now we literally have something we’re hearing about once a month. I think this golden era is divided into four buckets, Katherine, and that’s why I’m so excited for our patients and their caregivers.
Number one is novel JAK inhibitors. So, beyond the approved ruxolitinib, fedratinib, and now pacritinib, we have a fourth one that’s under consideration, that’s called momelotinib. Hopefully, we’ll have that approved by the end of the year. And there are actually other drugs around the world. So, not just in the U.S. and North America that are being developed as a further JAK inhibitor. So, just like we’ve seen in CML with the TKIs for BCR-ABL after the imatinib Gleevec medicine, hopefully, we have seven to 10 choices for our patients.
Number two is the combinatorial approach of a JAK inhibitor plus something else. And that’s a field that I’m personally very involved in and helping to lead. The concept there is you take the known workhorse drug, the JAK inhibitor, use it as the backbone, and then add in the second agent. We started to do those studies in patients who were already starting to lose a response and we added in the second agent, those were called suboptimal studies.
And then now we’re moving those drugs into the frontline setting in international global randomized studies. So, stay tuned, let’s see how those go. But the concept is, can you take a new agent, whether it’s a BET inhibitor, a bromodomain inhibitor, a Bcl-xL inhibitor, PI3 Kinase, et cetera, and combine it with the JAK inhibitor? The third bucket that’s even more exciting to many people is that of novel agents standing alone by themselves. Now you’ve had either a JAK inhibitor or some other therapy for your myelofibrosis. That didn’t work for whatever reason. Now you’re looking for a completely new strategy.
An explosion of research, not just in the lab, which we’ve had for the last 10 years, but over the last three or four years, amazingly, even despite the COVID pandemic. I would say dozens, really dozens of trials that are what you would consider beyond or non-JAK inhibitor therapy. Some of them include telomerase inhibition, with the imetelstat agent, for example. And so the concept here is, can you now hit the myelofibrosis in a completely different pathway?
And the answer clearly is yes. And those results have been tested now in the lower stages, the earlier stages, phase one and two. And you’re starting to see those drugs enter into the phase two and phase three. We eagerly await those results if there can be a viable beyond JAK inhibitor. And then finally, if that wasn’t exciting enough, there’s a fourth bucket, which is thinking about specifically the anemia myelofibrosis. We’ve never really historically done that. We’ve had older drugs, danazol, steroids, growth factor shots, blood transfusions.
But now here you see both pharmaceutical interest, as well as academic interest, in developing agents that either specifically target the anemia of MF or both, the MF and the anemia. And that could be a game changer for our patients in the next five years. So, Katherine, a wealth of exploding research that I’m personally very excited about that gives me and our field hope, momentum, and enthusiasm going into 2024.
Katherine Banwell:
Yeah. Well, Dr. Pemmaraju, as we close out our conversation, I wanted to end with a question that we usually start within our Thrive Series. In your experience, what does it mean to thrive with an MPN?
Dr. Pemmaraju:
Well, I really love that phrase so much because it’s meaningful to me.
You know, you’re talking about something that resonates with me and my patients, which is not just living with the MPN, but you’re talking about thriving with an MPN. That’s so resonant to us. I think really, I would go for three parts to that.
One is that it’s an acknowledgment or a complete understanding of the disease. So, not denial, the opposite of denial, whatever that is, Katherine. So, understanding as much as you can about the disease which is, I encourage people to Google, look up on the internet. I just, what I want you to do is couple that with talking about it in context with your provider. I think the worry that people have is you’re at your home midnight, you’re Googling stuff, it may or may not be right.
So, anyway, so just do that, but then bring the information to the next visit. So, fully understanding and learning as much as you can in your own way. Number two is to be able to have a quality of life that is not just living with the disease, but actually being successful at your relationships, your work, whatever it is that brings you meaning and joy in life. And that sometimes has to do with the MPN paradigm, sometimes has to do with the other stuff we said.
But I think, doing that, not despite the fact that you have the MPN, but acknowledging it with that, right? And then I think the third aspect is, if you have some way or some platform to be able to express yourself with the MPN because it’s such a rare disease, we think maybe only four out of 100,000 people worldwide get these. A lot of patients, not for everybody, by the way, but a lot of patients are thriving on support groups.
It used to be you have to be in person, that’s very difficult to do with rare diseases. But now online, social media, a lot of different ways to get involved. Whether someone’s an introvert or an extrovert, whether someone wants to be private or public, all those things are hugely important, so it’s a personal decision. But for many, they want to get out there, and it’s not necessarily this scientific information exchange, although that’s good. But the support and encouragement and comradery of talking to other patients about what we’re talking about.
It is, in fact, a little bit more facile to do it with the more common diseases, breast cancer, all of these things. And it’s much more difficult, social media online has opened that up. So, to me, I think that’s a kind of mix that I’ve been seeing in my patients. And that leads to empowerment. It leads to taking control of the things that can be controlled, leaving the things that can’t be controlled to what needs to happen. And then an understanding and anticipation of things that may happen in the next few visits, in the next few years. I think that’s how people can thrive with these MPNs.
Katherine Banwell:
Yeah. And that’s a hopeful message to leave our audience with Dr. Pemmaraju. Thank you so much for joining us today.
Dr. Pemmaraju:
Well, thank you, Katherine, and hats off to you and the team for not only keeping the advocacy and information going but during this pandemic time, becoming an essential source of information for our patients and getting the word out there. So, thank you.
Katherine Banwell:
Yeah, thank you. And thank you to all of our partners. To learn more about MPNs and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us today.
Thriving With an MPN | Managing Symptoms and Treatment Side Effects
Thriving With an MPN | Managing Symptoms and Treatment Side Effects from Patient Empowerment Network on Vimeo.
In this webinar, MPN specialist Dr. Naveen Pemmaraju, discusses strategies for managing symptoms and treatment side effects for people living with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Dr. Pemmaraju also shares advice for communicating with your healthcare team and provides an update on the latest MPN treatment and research.
Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.
Related Programs:
Understanding and Managing Common MPN Symptoms and Side Effects |
Thriving With an MPN | Advice for Setting Goals and Making Treatment Decisions |
Transcript:
Katherine Banwell:
Hello and welcome. I’m your host, Katherine Banwell. Today’s program is a continuation of our Thrive Series and we’re going to discuss coping with MPN symptoms and managing treatment side effects. Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you.
Let’s meet our guest today. Joining me is Dr. Naveen Pemmaraju. Dr. Pemmaraju, welcome. Would you please introduce yourself?
Dr. Pemmaraju:
Oh, thank you, Katherine and team. Just an honor to be here.
I’m Naveen Pemmaraju, a professor of leukemia at MD Anderson Cancer Center in Houston. And I also serve as one of our executive directors for the MD Anderson Cancer Network, and I specialize in MPNs and rare leukemia. So, happy to join you once again, Katherine.
Katherine Banwell:
Thank you so much for being with us today, taking time out of your schedule. Well, Dr. Pemmaraju, when it comes to living and thriving within an MPN, managing disease symptoms and treatment side effects is a big part of that. How can symptoms and side effects impact life with an MPN?
Dr. Pemmaraju:
Katherine, I’m glad you asked about that because I think before we get into the science and the pathobiology and all these complex things, it really starts with the patient. And as you and your team and others have really noted, the MPN for many of our patients, it is a chronic, often lifelong journey. And we really need to reemphasize in this modern era, the patient-centered experience and the caregiver experience.
And so I would emphasize a few things. One is that our MPNs are oftentimes so-called invisible diseases to other people. So, this phrase that just really is tough for us to hear for our patients and our loved ones, oh, you don’t look that you’re sick. You don’t look like you have cancer. So, it emphasizes the internal part of the internal medicine, that’s one. Number two, it reminds you that you cannot tell on the external what kind of a war, a cytokine war that is going on inside of a patient. And so even though the blood counts are normal, the spleen is okay, the treatment paradigm is going okay, we don’t know what’s really going on. So, that’s why our great friend and colleague Ruben Mesa invented and pioneered the MPN symptom burden to really nail down what’s going on.
And then third is our treatments, Katherine, our treatments, while overall halting or stopping or helping the MPN can then introduce a whole other round of toxicity, side effects, and so we need to manage that.
So, both the disease itself and the treatments, two separate entities, and that’s what we need to be monitoring in the clinic.
Katherine Banwell:
All right, well, thank you for that. As we get into the discussion, Dr. Pemmaraju, it’s important to note that some of the issues we’ll be talking about today are symptoms of the MPN, and others may be treatment-related side effects. So, let’s start with side effects. What are the most common issues associated with the main MPN treatment classes? Let’s start with JAK inhibitors.
Dr. Pemmaraju:
Oh, very nice. Yeah, that’s exactly the way I think about it too. So, with our JAK inhibitors, we now have 10 years since the approval of the ruxolitinib, the first in class. And now we have two more approved agents which are known as fedratinib (Inrebic) and pacritinib (Vonjo), and hopefully a fourth agent, momelotinib, which is under regulatory review at this time.
[Editor’s Note: Momelotinib (Ojjaara) was approved by the U.S. Food and Drug Administration (FDA) on Sept 15, 2023 for the treatment of intermediate- or high-risk myelofibrosis, in adults with anemia.]
So, we have a whole class of drugs. They have some similarities and then some differences, but in general, the JAK inhibitor class are well-tolerated drugs, but each of them has some side effects.
I’d like to go through them just as a top-line overview. It’s very important. Number one for the ruxolitinib agent, the one that’s been around longest. This one is usually well-tolerated as we said, but you do have to look out for a few things. Non-melanoma skin cancers can be increased in some of our patients, so the importance of dermatology and skin evaluations. Some infections such as viral herpes, zoster, and shingles, so we need to be aware of that. And then weight gain, weight gain is something that we’re seeing more over time as we appreciate the drug, particularly as we move it into earlier lines of therapy, such as p.- vera.
As I look at the other agents, the fedratinib already carries an FDA black box warning for an encephalopathy syndrome, thought to be Wernicke’s encephalopathy, which can affect the brain. But really an encephalopathy syndrome, which means we have to check thiamine levels and replace them and be aware of that. That’s vitamin B1 and also GI side effects with that agent. And then finally, the pacritinib agent has a few toxicity and side effects.
Again, all these are on the package label insert, well-known. Some GI side effects, particularly in the first few months, including diarrhea, and we need to watch out for bleeding and these kinds of effects, especially in the opening days and weeks of the agent. So, again, JAK inhibitors, well-tolerated class, oral medicines, but can have some notable side effects that we have to follow together in the clinic.
Katherine Banwell:
What about interferon? What are some common side effects?
Dr. Pemmaraju:
Yeah, great. So, the interferon class, which actually now is a class of drugs. We started out as let’s call it the regular Interferon, which was multiple times a week dosing. Then the Pegylated Interferon, which went down to once a week. And then now we have the ropeginterferon (Besremi), which is the recently approved agent in p. vera, which is every two weeks spaced out to every month.
So, as you said, in this class of drugs, what’s old is new again. These drugs have actually been around longer than the JAK inhibitors, interestingly. You do have to be mindful. These are a very serious set of drugs. We usually set aside a good amount of time to talk about the side effects, and they are many historically.
The main ones include psychiatric neurological side effects. So, it can cause a depressed mood, change in the mood, even depression. Hugely important, so everyone needs to be aware of that, including the caregivers. It can cause autoimmune side effects, so such as thyroid, liver, these type of side effects. And then finally, of course, any of these Interferons can cause a flu-like profile, you know, not feeling well, particularly in the beginning days.
So, we usually try to mitigate it with lots of education to the patient, the caregiver, remind all members of the team. If you can, maybe even start at a low dose and escalate up, which is what we’re trying to do in the clinic. And then really close monitoring for stuff that you can monitor, the thyroid, the liver, the mental side effects, as we said. Usually most of our patients over time, most of them do get used to the drug. So, there is some kind of an immune component to it, but you can have side effects at any time.
I would say also, Katherine, that these later forms of the Interferon continue to improve. And so we’re seeing either less and less side effects or at least better managed, better tolerated, more understanding of these. So, a great class of drugs. And I should also say that our colleagues around the world are starting to combine the two classes of drugs for patients with myelofibrosis. And so we need to be paying attention to those combinatorial approaches.
Katherine Banwell:
What about hydrea?
Dr. Pemmaraju:
Yeah, right. Yeah, so hydroxyurea, we also have to mention that.
One of the workhorse medicines of our field. We use it in all the MPNs.
Again, an older class of drugs such as the Interferons that have been around prior to the JAK inhibitors. Used in a variety of diseases, both benign and malignant, used in sickle cell anemia. Historically has been used in both blood and solid tumor cancers, but we use it very commonly in MPNs. Almost all of our viewers are familiar. Hydroxyurea is not a benign drug. It is a chemotherapeutic agent. You know, you have to handle it with care.
And so it’s got a few side effects. It can cause some fatigue in some patients. One of the more notable classical side effects is an ulcer formation, either in the mouth area or in the lower extremities, such is in the feet, so, you know, grossly visible. It can cause some fever and not feeling well in some patients. I will say again, a lot of these drugs are generally well tolerated. Most of our patients are 60, 70, 80, and older, but you can certainly have those side effects. A lot of these drugs, Katherine, can affect the skin.
I did mention that earlier. So, ruxolitinib, even the interferons, hydrea, they can all cause skin lesions, maybe some of them associated with non-melanoma skin cancer, such as squamous cell and basal cell. So, one amazing part of the practice has been close association with our dermatology colleagues, not something I would have expected 10, 15 years ago. And that’s been a helpful part of the practice.
So, I think it’s a point where I can emphasize that, in addition to having us as the MPN or blood cancer team, Katherine, the pandemic has reminded us the importance of primary care team as well. So, it’s really two teams, someone checking the cholesterol, cancer screenings, skin checkups, mammogram, PSAs. And then in coordination with your MPN team and then everyone working together, so colonoscopies, et cetera. So, just a plug there, especially the last three, four years where people have gotten behind to make sure that we’re keeping up with that part of the deal as well.
Katherine Banwell:
With all the testing, yeah.
Dr. Pemmaraju:
Exactly, right.
Katherine Banwell:
You mentioned a couple of treatment side effects and how they’re managed, but in general, across the board, are treatment side effects managed in the same way, in similar ways?
Dr. Pemmaraju:
Now, that’s a great question. So, here I’ve given you this nice list, kind of academic version of the list, but boy, no, right. And all my patients and everyone out there knows that there’s some varied practices. You know, the varied practices are not only, as you say, across the country and across the world, but also even in our own clinics, patient to patient. The MPNs have humbled and taught us that one person’s MPN can be starkly different from the next, so on and so forth.
So, I’m not just talking about the difference between PV, ET, myelofibrosis, and systemic mastocytosis. I’m talking about one person’s MF is completely different than the other. I think there are a couple of things I didn’t mention. So, pruritus, or itching is one of the great symptoms really. It’s not a side effect usually, but it’s a symptom of the MPN. There are some ways to treat that in the clinic.
Fatigue really has no great way to treat it. Usually when you introduce one of the JAK inhibitors that can improve. On the side effects side, as we were mentioning, a lot of these are unsatisfying things. The flu-like symptoms of the interferon, the weight gain of the JAK inhibitor. So, I think what you’re saying is so correct, and let me admit it, I’m going to be the first to admit it, there’s not really a good standard playbook.
But on the other hand, I think personalization. As we’ve always said, in our rare disease space, if you have a disease, it’s not rare to you. It’s what you have, it’s what your spouse is dealing with, your loved one, your mother with you. And so, I would advocate here that there’s a personalized playbook there. I would say that there are three guiding principles though. One is when you have side effects of a medicine, the first thing to do is let your healthcare provider team know. I know that sounds obvious, but here I am in the clinic and sometimes we don’t find out until later.
And so some of that is because the patient says to themselves, let’s tough it out. Or they may not know, or they may not be able to, or it may not be easy to communicate with our healthcare teams. Two is when you’re evaluating, every patient’s case is different. This is not specific advice, as you said, at the top of the hour here. But in a general sense, you really need to evaluate if the side effect is peculiar or particular to just that patient case, so idiosyncratic, unpredictable, notable.
Or, is it a general expected sort of something that you thought could already happen and then go with it from there? And then finally, the concept of dose interruptions, dose reductions, treatment holidays, something very important. So, basically a lot of different ways you can go, but no standard or uniform playbook in our MPN field, as you and the team well knows.
Katherine Banwell:
Thank you for that Dr. Pemmaraju. I’d like to move on to common MPN symptoms now. Let’s start with myelofibrosis. What are the symptoms associated with this particular MPN?
Dr. Pemmaraju:
Excellent question. So, for the myelofibrosis, generally thought to be our most advanced of the MPNs, can be low risk, intermediate to high risk. We’ll focus our comments here on intermediate to high risk, the more advanced MF. This is important because not only what I’m going to tell you is sort of a subjective list of symptoms, but because of the work of my great friend, Ruben Mesa, who pioneered the MPN symptom burden, we’ve actually been able to, as he and I say, quantify the unquantifiable.
So, take subjective information and turn it into objective. For example, we know that among the three MPNs, PV, ET, and MF, that fatigue is by far the most common symptom that our patients report. It’s a fatigue that’s more than the general feeling tired at the end of the day. It’s sometimes a wiped-out fatigue. Some of our patients will have pruritus or itching. Many of our patients will have early satiety, which means getting full too early because either the spleen is too big, decreasing the appetite. Bone pain and neuropathy can happen in our MF patients. Brain fog and decreased concentration, huge issue among a lot of our patients.
And finally, because of the low blood counts, if a myelofibrosis patient is anemic, they can have those issues. So, fatigue, shortness of breath, even chest pain and palpitations. If the platelets are too low, or too high for that matter, bleeding or clotting.
So, the problem with myelofibrosis, it ranges the gamut from the low-risk patients, who can be treated maybe even as a PV or ET observation or not as advanced treatment paradigm, all the way to intermediate high risk where patients are cachectic, losing weight, not feeling well, drenching night sweats. And all of these can be captured on not only the scoring systems but also the symptom burden scales. And to be honest with you, this is the majority of what our patients are feeling outside of the blood counts and outside of the objective information. So much so to the point, Katherine, where a patient can present with these symptoms solely, without ever having a blood count or a bone marrow or anything, and then it leads to the work of it.
Katherine Banwell:
Oh, wow. Wow, fascinating. What about symptoms for polycythemia vera?
Dr. Pemmaraju:
Yeah, so this is a great theme that you’ve got going here, which is know your body. If you know your body, then you’re able to tell what’s abnormal or normal. p. vera can be a bit more subtle.
Oftentimes patients with p. vera can have a normal life expectancy and the longer term series in Europe show that it’s basically about the same life expectancy as the general population or slightly lower. But that doesn’t tell the whole story. Patients with p. vera can have an unbelievable symptom burden, either from the hyperviscosity of the hematocrit, the blood level being too high or the cytokine storm, that I mentioned, that makes people feel not well. So fatigue, brain fog, feelings of sluggishness, feeling too full, those are common in p. vera.
The treatments are aimed at trying to make that better. So, phlebotomy to bring the hematocrit down below 45 can make you feel a little bit lighter, a little bit better, decrease the brain fog. If you’re using either the standard treatments of hydrea or Interferon, and then, of course, the baby aspirin to prevent clots, heart attacks, stroke. The newer agents in p. vera include the ropeginterferon that we mentioned earlier, clinical trials, such as the PTG-300 that I’m a part of, that try to really keep the blood levels normal all the time.
And so hopefully help to improve the quality of life, decrease the chance of having a clot, and also hopefully try to make patients feel better from these aspects.
Katherine Banwell:
What about essential thrombocythemia or ET?
Dr. Pemmaraju:
ET, again, just like PV, you can have a lot of patients who are either incidentally diagnosed or not too much of a symptom burden. But again, here, the blood counts don’t tell the story. You can have “low risk ET” which is defined as less than 60 or no prior blood clots. So, you can be 43 years old, diagnosed with ET, your blood counts aren’t that high, but yet you’re still feeling overwhelming fatigue, itching. You’re seeing flashing things in your eyes called scotomas. You’re having small nerve or vascular issues called erythromelalgias. It’s a very elusive and difficult disease, particularly for our young patients. So, in ET, again, the same set of symptoms can happen. This fatigue, itching, the brain fog, concentration, bleeding, and or clotting.
And so again, the goal of therapy is to mitigate those. If you’re young, a lot of patients are either observed or baby aspirin. If you’re older than 60 or have high risk features, then again, cytoreductive therapy. The other aspect I should mention is you can start out with one of these and it transforms into the other. That’s called clinical or phenotypic shifts. You can start out as an ET, go to PV. You can start out as PV and go to myelofibrosis. You can start out as myelofibrosis and go to acute myeloid leukemia. So, that’s why follow-up, even over years, decades, is important, preferably with an expert team, because you never know when one of these things wants to transform. And then your side effect, or I should say your symptom profile therefore changes with that transformation.
Katherine Banwell:
Well, it’s obvious that there’s some symptom overlap along with this.
Dr. Pemmaraju:
Right.
Katherine Banwell:
And so I’m wondering what the strategies are for managing these. Let’s start with fatigue first.
Dr. Pemmaraju:
Let’s do that.
Katherine Banwell:
How do you manage that?
Dr. Pemmaraju:
This is one of the tougher parts of what we do. I’m glad you’re pinning me down to say it because really this is the majority of what we need to be talking about in the clinic. I’m going to just be honest, you know, with all the scientific breakthroughs and everything, some of these are limited. The fatigue, this is some of the strategies I use and some of the experts in the field. I think one is managing the underlying disease. So, as you mentioned, if you have high-risk, intermediate to high-risk myelofibrosis, one of the great findings of our field is the JAK inhibitor class generally helps to improve symptom burden.
So, that is the splenomegaly, the fatigue, the pruritus. Maybe not so much the itching, but some of these other things. So, I think treating the underlying disease, that’s okay. Number two is many clinics, Onc centers around the country are starting to open up a supportive care or fatigue center clinic. So, I am referring several of my patients there, we’re talking about diet, nutrition, exercise. We used to never talk about these things. Ruben Mesa has found that doing yoga and meditation can genuinely actually help the pathobiology to reduce the cytokine storm and improve the fatigue and quality of life.
Dr. Angela Fleischman, our colleague at UC Irvine, has done work suggesting that possibly an antioxidant diet such as the Mediterranean diet can help the overall general fatigue, well-being, wellness. And then of course I mentioned earlier, but I’ll mention here too, sometimes fatigue is outside of the MPN. Have you had your TSH or thyroid checked? What about your vitamin D levels? How are you doing on these PCP general checks? Things that may be contributing to the life and the happiness.
And finally, let me make a plug for mental health. I don’t know how much we were emphasizing before the COVID pandemic, but after, the last three or four years have been tough. Healthcare providers, caregivers, patients themselves, mental health checkup, that can also be contributing to fatigue, not getting out of bed, in addition to the organic medical problems. So, let me advocate a multifactorial approach, scientifically summed up as treating what you can with the underlying MPN, fine, treating the side effects and symptoms of the MPN, as you said.
And then, other, which can be a huge bucket, particularly as we get older, to not forget about that. Again, checking the thyroid level. And then when you’re on these different treatments, you can personalize it. Interferon, obviously, has its own separate set of side effects and then of course the other agents. So, I think that may be the best way to approach it. Maybe a three-bucket approach. The MPN itself, and then the treatment itself, and then the other, something like that.
Katherine Banwell:
Yeah, yeah. And as you’ve mentioned, it’s all going to be personalized and individualized, because what’s going to work for one person is not necessarily going to work for another.
Dr. Pemmaraju:
Hear, hear, well said to that. You know, you think you make a great diagnosis in the clinic, someone’s having fatigue, they’re on therapy for your MPN. You check the TSH, it’s wildly abnormal. Okay, you refer them to endocrine. Six months later, the thyroid level is completely normal now on thyroid medicine. And yet, the fatigue, brain fog, everything is still not clear.
The MPN is under good control. What gives? That’s the difficult part of these diseases. So, I really love what you said about the personalization and to keep looking and keep trying.
Katherine Banwell:
What might an increase in symptoms mean? Does it mean that the disease is progressing or that maybe it’s time to change therapies?
Dr. Pemmaraju:
Yeah, possibly. So, with all this objective evidence, there’s different buckets of disease progression. And some of them are objective and obvious, rising spleen, increasing blasts, or leukemia cells in the peripheral blood. The start of transfusion dependency for either anemia or platelets that weren’t there before. Sometimes, there are obvious things that you can point to, but there are a couple of scenarios where it’s not as obvious. You just named one. One is increasing symptom burden profile. You see, sometimes you have to think about, is it the sequela of the treatment itself or is it disease progression?
I’ll give an example. If you start on an Interferon product and the dose is too high, you may be feeling not so great from the Interferon. But maybe in that case, a simple dose reduction was the answer because then you’re still getting the anti-disease activity, less side effects and all that. So, I’ll answer your question by saying possibly, but it can’t be the whole story. So, increasing symptoms is a harbinger, it’s a red flag. In the clinic, it means pause. Workup, is this a subject of the treatment itself? Is it because the disease is progressing? Do we need to do a restaging and workup, whether that means a bone marrow biopsy, whatever that means?
Or again, let’s put that other in there. What about the other comorbidities? Do you have class one heart failure, that’s now class three and you’re retaining fluid? And that’s why you’re short of breath and you actually need an echo and a cardiologist and an evaluation of your diuresis. So, I think that’s important, but the key is don’t blow it off, right? So, increasing symptom in MPN is telling you something isn’t right, and we need to check it out.
Katherine Banwell:
Right, and for the patient, tell your healthcare team about it.
Dr. Pemmaraju:
Communicate always. I think what we see is people are so proper and so compassionate and so kind and collegial, and that’s beautiful. But actually in the MPNs and all these rare blood cancers where so little is known and so little is obvious, communication is the key.
Katherine Banwell:
Yeah. I’d like to make some time now to answer questions from the audience.
Dr. Pemmaraju:
Great.
Katherine Banwell:
And here are a few we received prior to the program. Stephanie writes, I have ET and I’m not being treated. Do you have advice for the watch and wait period? I’m anxious about the disease changing and don’t know what I’m waiting for. So, before you answer the question, Dr. Pemmaraju, would you define this term, watch and wait?
Dr. Pemmaraju:
I will. And to Stephanie and everyone out there, this is a great question. I will say half the folks I talk to actually call it watch and worry, okay. Some people call it watch and wait, and as Stephanie’s saying, some people call it watch and worry.
Yeah, the concept is threefold. One is that there are many cancers, many cancers, including blood cancers, that can be caught so early on that they don’t require treatment. A lot of patients with CLL, chronic lymphocytic leukemia, ET, as Stephanie mentioned, in the solid tumor. It’s very common to be diagnosed with a prostate cancer that’s low grade, early stage that can be observed. Number two is in ET, there is a science behind it.
What we found in our studies, and they can be updated over time and you’ll see those, the traditional is that if you’re below the age of 60 and/or you’ve had no blood clot, thrombotic event, that’s considered low risk. And the treatment can be observation, perhaps adding in a baby aspirin to prevent against blood clots if there’s no contraindication. Now what’s magic about that age 60, obviously as you know, it’s not magic. It’s more of a statistical, continuous variable algorithm that says around that time, the risk of blood clots goes up. And so then you’d consider cytoreductive therapy at that point. Now there’s exceptions to that.
Many of our young patients are on therapy, but there’s usually some reason for that. Some high-risk feature, wildly uncontrolled blood counts, for example, symptom burden, some other high-risk features. So, it’s a suggestion. It’s a guideline, not an absolute. And then the third part of it is, the what do you do in that time? And that’s the frustrating thing. And I think that’s what Stephanie’s getting to.
Again, that’s why I said the watch and worry versus watch and wait. Some of it is, how are you feeling outside of this? Some patients take it as a great news. Hey, you have this blood cancer, that’s not good news. But the good news is it’s probably not going to be active for a long time, we can, “just watch it.” But some people, as Stephanie is saying, take it the opposite way. What do you mean I got a blood cancer? I got something lurking in my body. You’re telling me it’s there, you know it’s there. And so what’s up with that? And the concept there is that some of these situations like low-risk ET, we found that if you treat too early, too aggressively, you can actually do harm.
Katherine Banwell:
Oh.
Dr. Pemmaraju:
So, that’s the key. These chemo drugs are not benign as you had me discuss earlier. They have toxicity, side effects, short-term, long-term. So, it’s a risk-benefit thing. If the risk far outweighs the benefit, as in the younger patient with no symptoms, no high-risk features, observation is okay. But at some point, when it turns, that’s the threshold.
So, really the key is, if we believe these are stem cell blood cancer disorders, we need to be thinking about and designing therapies with minimal to no toxicity. Something that actually modifies the disease early on and something that leads to long-term outcomes. And we don’t have that yet in ET. We’re working on that in PV and myelofibrosis. So, stay tuned for that. And then finally, let me also add, this is an important point, not everybody gets it. This watch and wait versus watch and worry. So, I’m glad Stephanie brought that up because it’s not always good news, uniformly, when you tell someone, good news is you don’t have to do anything bad news, there’s something there.
Katherine Banwell:
Right. Jess wrote in with this question. I’ve been experiencing bone pain and neuropathy. Is there anything that can eliminate or reduce these symptoms?
Dr. Pemmaraju:
Great question, and it ties into our earlier question about the MPN symptom burden. On the original MPN-10 scale that Ruben and others pioneered, you will see both of those. You will see the bone pain, neuropathy.
Now there’s been, you know, different narrowing down of these questionnaires and things, but in general, our patients do have these and that’s across the board. So, not only myelofibrosis but also our patients with PV and ET. These are among the most frustrating, I would say. Again, as you would expect, if you are advanced enough and you’re getting treatment, you hope that the treatment itself, whether it’s the Interferon or the JAK inhibitors or whatever you’re doing, clinical trial, hopes to alleviate those. But it doesn’t all the time.
Then the second issue is, these are likely the result of a cytokine storm or increased cytokines, these protein messengers that are abnormally high in our patients with MPNs. There’s varying unsatisfying things that people do. Sometimes we give antihistamines for people with bone pain. So that’s these over-the-counter sinus allergy medicines. Interestingly, the Claritins and the Zyrtecs, these type of medications, that can sometimes help in MPN bone pain. And then also for the neuropathy, these common neuropathy drugs that everybody knows, the gabapentins and all of these drugs are used frequently.
There’s no doubt in my clinic and everybody else’s, but the varying levels of success. So, I think it speaks to the fact that these two are kind of from the MPN itself. And treating the underlying MPN is still usually your best strategy, using these, borrowing these medications, from the other aspects.
And then finally, my other plug here, which has kind of been a theme here, hopefully it resonates, and it doesn’t sound generic or unnecessary, is these things can sometimes be something else. Okay, bone pain and neuropathy can be something else. So, we do have cases of people having frequent falls, really serious stuff. In those cases, I refer those patients to a neurologist. Nerve conduction studies right, very advanced studies in the couple of cases that are so severe that it’s beyond thinking that it’s just due to the MPN.
Katherine Banwell:
Dr. Pemmaraju, as a researcher, what are new and emerging therapies on the horizon in MPN care?
Dr. Pemmaraju:
Well, Katherine, I’m glad you asked because I’m proud to tell you here, at the end of 2023, that we’ve now entered a new golden era of therapies for MPNs. Your group, and others, have led the way in advocating, but for so many years, honestly, we didn’t have many breakthroughs or new medicines. And now we literally have something we’re hearing about once a month. I think this golden era is divided into four buckets, Katherine, and that’s why I’m so excited for our patients and their caregivers.
Number one is novel JAK inhibitors. So, beyond the approved ruxolitinib, fedratinib, and now pacritinib, we have a fourth one that’s under consideration, that’s called momelotinib. Hopefully, we’ll have that approved by the end of the year. And there are actually other drugs around the world. So, not just in the U.S. and North America that are being developed as a further JAK inhibitor. So, just like we’ve seen in CML with the TKIs for BCR-ABL after the imatinib Gleevec medicine, hopefully, we have seven to 10 choices for our patients.
Number two is the combinatorial approach of a JAK inhibitor plus something else. And that’s a field that I’m personally very involved in and helping to lead. The concept there is you take the known workhorse drug, the JAK inhibitor, use it as the backbone, and then add in the second agent. We started to do those studies in patients who were already starting to lose a response and we added in the second agent, those were called suboptimal studies.
And then now we’re moving those drugs into the frontline setting in international global randomized studies. So, stay tuned, let’s see how those go. But the concept is, can you take a new agent, whether it’s a BET inhibitor, a bromodomain inhibitor, a Bcl-xL inhibitor, PI3 Kinase, et cetera, and combine it with the JAK inhibitor? The third bucket that’s even more exciting to many people is that of novel agents standing alone by themselves. Now you’ve had either a JAK inhibitor or some other therapy for your myelofibrosis. That didn’t work for whatever reason. Now you’re looking for a completely new strategy.
An explosion of research, not just in the lab, which we’ve had for the last 10 years, but over the last three or four years, amazingly, even despite the COVID pandemic. I would say dozens, really dozens of trials that are what you would consider beyond or non-JAK inhibitor therapy. Some of them include telomerase inhibition, with the imetelstat agent, for example. And so the concept here is, can you now hit the myelofibrosis in a completely different pathway?
And the answer clearly is yes. And those results have been tested now in the lower stages, the earlier stages, phase one and two. And you’re starting to see those drugs enter into the phase two and phase three. We eagerly await those results if there can be a viable beyond JAK inhibitor. And then finally, if that wasn’t exciting enough, there’s a fourth bucket, which is thinking about specifically the anemia myelofibrosis. We’ve never really historically done that. We’ve had older drugs, danazol, steroids, growth factor shots, blood transfusions.
But now here you see both pharmaceutical interest, as well as academic interest, in developing agents that either specifically target the anemia of MF or both, the MF and the anemia. And that could be a game changer for our patients in the next five years. So, Katherine, a wealth of exploding research that I’m personally very excited about that gives me and our field hope, momentum, and enthusiasm going into 2024.
Katherine Banwell:
Yeah. Well, Dr. Pemmaraju, as we close out our conversation, I wanted to end with a question that we usually start within our Thrive Series. In your experience, what does it mean to thrive with an MPN?
Dr. Pemmaraju:
Well, I really love that phrase so much because it’s meaningful to me.
You know, you’re talking about something that resonates with me and my patients, which is not just living with the MPN, but you’re talking about thriving with an MPN. That’s so resonant to us. I think really, I would go for three parts to that.
One is that it’s an acknowledgment or a complete understanding of the disease. So, not denial, the opposite of denial, whatever that is, Katherine. So, understanding as much as you can about the disease which is, I encourage people to Google, look up on the internet. I just, what I want you to do is couple that with talking about it in context with your provider. I think the worry that people have is you’re at your home midnight, you’re Googling stuff, it may or may not be right.
So, anyway, so just do that, but then bring the information to the next visit. So, fully understanding and learning as much as you can in your own way. Number two is to be able to have a quality of life that is not just living with the disease, but actually being successful at your relationships, your work, whatever it is that brings you meaning and joy in life. And that sometimes has to do with the MPN paradigm, sometimes has to do with the other stuff we said.
But I think, doing that, not despite the fact that you have the MPN, but acknowledging it with that, right? And then I think the third aspect is, if you have some way or some platform to be able to express yourself with the MPN because it’s such a rare disease, we think maybe only four out of 100,000 people worldwide get these. A lot of patients, not for everybody, by the way, but a lot of patients are thriving on support groups.
It used to be you have to be in person, that’s very difficult to do with rare diseases. But now online, social media, a lot of different ways to get involved. Whether someone’s an introvert or an extrovert, whether someone wants to be private or public, all those things are hugely important, so it’s a personal decision. But for many, they want to get out there, and it’s not necessarily this scientific information exchange, although that’s good. But the support and encouragement and comradery of talking to other patients about what we’re talking about.
It is, in fact, a little bit more facile to do it with the more common diseases, breast cancer, all of these things. And it’s much more difficult, social media online has opened that up. So, to me, I think that’s a kind of mix that I’ve been seeing in my patients. And that leads to empowerment. It leads to taking control of the things that can be controlled, leaving the things that can’t be controlled to what needs to happen. And then an understanding and anticipation of things that may happen in the next few visits, in the next few years. I think that’s how people can thrive with these MPNs.
Katherine Banwell:
Yeah. And that’s a hopeful message to leave our audience with Dr. Pemmaraju. Thank you so much for joining us today.
Dr. Pemmaraju:
Well, thank you, Katherine, and hats off to you and the team for not only keeping the advocacy and information going but during this pandemic time, becoming an essential source of information for our patients and getting the word out there. So, thank you.
Katherine Banwell:
Yeah, thank you. And thank you to all of our partners. To learn more about MPNs and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us today.
Becoming an Empowered and [ACT]IVATED MPN Patient
Patient Empowerment Network (PEN) is committed to efforts to educate and empower patients and care partners in the myeloproliferative neoplasm (MPN) community. MPN treatment options are ever-increasing with research advancements in treatments and testing, and it’s essential for patients and families to educate themselves with health literacy tools and resources on the latest information in MPN care. With this goal in mind, PEN kicked off the [ACT]IVATED MPN program, which aims to inform, empower, and engage patients to stay abreast of up-to-date information in myeloproliferative neoplasm care.
The [ACT]IVATED MPN program is aimed at newly diagnosed MPN patients, yet it can help patients at any stage of disease. [ACT]IVATED MPN helps patients and care partners stay updated on the latest options for their MPN, provides patient activation tools to help overcome care disparities and barriers to accessing care, and powerful tips for self-advocacy, coping, and living well with a blood cancer.
Myeloproliferative Neoplasm Disparities
Race or ethnicity may have an impact on some health conditions, including MPNs. Cancer patient Lisa Hatfield interviewed Dr. Idoroenyi Amanam, Assistant Professor in the Division of Hematology at City of Hope. He explained about MPN risks and outcomes that may be impacted by patient race or ethnicity. “…we know that if you have high blood pressure, you have a higher risk for these complications-associated MPNs. And we know that African American males have a higher risk for that, so I think those things are…that example is a clear indicator that really identifying these basic risk factors that are related to diet, exercise, your weight, and other behavioral, possibly behavior-related factors may put you at higher risk to have complications from MPNs.”
Dr. Amanam further shared research findings and what needs further study to draw conclusions. “We have looked at incidences of thrombotic events in patients who have MPNs, and we tried to see if there was a difference between racial groups, and we didn’t. We did see that if you’re younger, you do have a higher risk of thrombosis over time, but there was no difference for if you were white, Hispanic, or African American. What we did find though, in a small single center study is that if you are non-white, there’s a higher risk of death over time. And I think we still need a lot of work to get a better understanding as to why that’s the case.”
Solutions for Improved Myeloproliferative Neoplasm Care
Clinical trials are key in moving MPN research forward to improved treatments and care. Dr. Amanam shared his perspective about other players besides patients who can help move the needle forward. “I think that going back to the idea that we want to practice the best science, we want to be able to publish the best data. The responsibility is on the clinicians, the scientists, the clinical trialists, the drug companies, the institutions to really be able to structure clinical trials that are relevant to our real world experience. And so how can we better encourage that? I think from a government perspective, potentially incentivizing drug companies and institutions and the other major players that really are involved in pushing this field forward to practice better science.”
Dr. Amanam expanded on how clinical trials can be diversified. “And once we’re clear that being able to have a diverse participant pool will give us the best results and therefore will lead to your drug being approved. I think we will have more participants from all groups.”
Some underrepresented patient communities may experience obstacles to MPN care. MPN Nurse Practitioner Natasha Johnson from Moffitt Cancer Center provided advice to help patients. “Patients themselves can research clinical trials by looking at clinicaltrials.gov and see what’s out there and contact the academic center that’s performing those trials. There’s free information online that provides recorded sessions from conferences or speakers or speaking done by the MPN experts that you can just look to and get to easily to help understand the disease, knowing the symptoms, and then guiding treatment.” Natasha Johnson continued with additional advice for optimal care. “.…to try to get into a large cancer center or academic center and see an MPN expert. Many times, this is just by self-referral. Charity is sometimes provided through these. Zoom visits can be done as consults or follow-up visits. So my encouragement would be search these out, find out who the experts are, and contact them directly and see if there is any possibility or a way that you can get in to see an MPN expert for a consult so you can get the best care possible.”
Signs of MPN disease progression is something that patients and providers must be on the lookout for. Natasha Johnson shared her advice for patients to empower themselves against disease progression. “…monitor your blood cell counts, be your own advocate. Think about if they’re changing, could it be medication, or is it disease progression? Monitor your symptoms. Look at the total symptoms score or write down your symptoms and try to record where you’re at in intervals. Are things getting worse? If they are, don’t wait three months for your next appointment. Contact your healthcare provider and ask to be seen. Ask about getting a repeat bone marrow biopsy to establish where the current disease status is because that can open up doors possibly to more treatments.”
The future of MPN care has an additional approach to address. Dr. Amanam shared his perspective and how patients can help advocate for improved treatments. “I think in the next three to five years, we’re going to have drugs that are going to actually be able to treat the underlying disease before it gets to a point where you may need more aggressive therapy…And so it’s exciting where we’re going, and I think the questions that as a patient that I would ask are, because of the fact that we only have few FDA-approved therapies, are there any clinical trials that are able to target the underlying disease as opposed to just treating the symptoms? I think that’s very important for the patients to ask, especially in this space now.”
Rates for stem cell transplant approvals must improve for lower income groups and for African American and Hispanic groups to provide better health outcomes for blood cancers like MPNs. Dr. Amanam explained what’s involved with transplants and how others can help as donors. “You can donate your bone marrow, or you can donate your stem cells that are not inside of your bone marrow. And typically as a donor, your experience of actually donating is about a day. And the recovery time after you donate your bone marrow or stem cells, it’s typically within about one to three days. So the benefit of donating your stem cells or bone marrow outweighs the inconvenience of a day or a couple of days of your schedule being altered. So I think that’s really important to understand. And I think if we can get more people to be aware of this, I think we can definitely get more donors.”
[ACT]IVATED MPN Program Resources
The [ACT]IVATED MPN program series takes a three-part approach to inform, empower, and engage both the overall MPN community and patient groups who experience health disparities. The series includes the following resources:
- Myeloproliferative Neoplasm Basics for Newly Diagnosed Patients
- Are MPN Risks and Outcomes Impacted by Race or Ethnicity?
- What Does the Future of Myeloproliferative Neoplasm Care Look Like?
- Are There Any MPN Disparities in Subtypes and Genetics?
- Have MPN Disparities Been Addressed by Institutions?
- MPN-Related Complications | Are BIPOC Patients at Higher Risk?
- How Can MPN Clinical Trials Be Diversified?
- Understanding MPN Treatment Goals and Shared Decision-Making
- Are There Disparities in Stem Cell Transplant Outcomes?
- Bone Marrow Registries | What Myeloproliferative Neoplasm Patients Should Know
- Graft-Versus-Host Disease Risk for BIPOC Patients
- Emerging MPN Therapies in the Research Pipeline
- How Can Myeloproliferative Neoplasm Care Barriers Be Overcome?
- Myeloproliferative Neoplasm Financial and Care Resources
- How Can Underrepresented MPN Communities Access Support?
- [ACT]IVATED MPN Resource Guide
- [ACT]IVATED MPN Resource Guide en español
- [ACT]IVATED MPN Patient Vignettes
- [ACT]IVATED MPN Activity Guides
Though there are myeloproliferative neoplasm disparities, patients and care partners can take action to empower themselves to help ensure optimal care. We hope you can take advantage of these valuable resources to aid in your MPN care for yourself or for your loved one.
[ACT]IVATED MPN Resource Guide en español
[ACT]IVATED MPN Resource Guide
Managing Life With an MPN | What You Need to Know
Related Programs:
Transcript:
Katherine Banwell:
Hello and welcome. I’m Katherine Banwell, your host for today’s program. Today’s webinar is a continuation of our Thrive series. And we’re going to discuss how to manage life with an MPN. Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you.
Let’s meet our guest today. Joining me is Dr. Raajit Rampal. Dr. Rampal, welcome. Would you please introduce yourself.
Dr. Raajit Rampal:
Hi. Thank you so much for having me. I’m Raajit Rampal from Memorial Sloan Kettering Cancer Center where I focus on myeloproliferative neoplasms.
Katherine Banwell:
Thank you so much for being with us today.
Dr. Raajit Rampal:
My pleasure.
Katherine Banwell:
As we do with each of the webinars in our Thrive series, let’s start with this question. In your experience, what do you think it means to thrive with an MPN?
Dr. Raajit Rampal:
It’s a great question, right. I think taking a step back, when we think about our patients with MPNs, one of the questions I always have for patients are what are your goals. And inevitably and invariably, people want two things. They want to live longer and they want to live better. And so, I think that thinking about thriving with an MPN to me is about how do we minimize the impact of an MPN in someone’s life. And that means a couple of things. One that means how do we deal with symptoms or things that are causing medical problems.
But two, how do we deal with the anxiety of a diagnosis? In many cases in my experience, that can be just as detrimental to somebody’s well-being as the actual physical symptoms of the disease.
Katherine Banwell:
When it comes to choosing therapy for polycythemia vera essential thrombocythemia, or myelofibrosis, it’s important to work with your healthcare team to identify what is going to work best for you. So, to begin, would you define shared decision making and why is this critical to properly managing life with an MPN?
Dr. Raajit Rampal:
Yeah. Shared decision-making, to me, is really about the physician or whoever is on the healthcare team providing the patient all of the information needed to make a good decision. That means what are we trying to do? What is the medication or invention going to accomplish? What are the side effects because there are always side effects.
And what do we think that’s going to do or how is that going to impact the patient’s life? Where things get nuanced is that patients come to us because we have expertise. There are two extremes. One extreme is that the physician says this is the medication you should take. End of discussion. The other extreme though is also not helpful, which is to say to a patient here are five choices. Here are the side effects. You pick one. Our job is to lay out those side effects and the benefits but then, also help guide a decision.
Katherine Banwell:
What are treatment goals and how are they determined?
Dr. Raajit Rampal:
It depends on the disease to a large extent. Now, when we’re dealing with ET and PV, the primary goal of our interventions is to reduce the risk of a clotting event or bleeding event. And that usually involves controlling the blood counts in some cases, not in all patients with ET.
Sometimes aspirin is all we do. Myelofibrosis is a little bit more complicated because it depends on what the problem is. Not all myelofibrosis patients have the same challenges. Some have anemia that needs treatment. Some have a big spleen. Some have symptoms and some have nothing and they just need observation. So, it’s a bigger list with MF patients. But I think the first part of the discussion always is defining what the goal needs to be.
Katherine Banwell:
What factors are considered when choosing therapy for ET, PV, and MF?
Dr. Raajit Rampal:
I think a couple of things. One is what medication we think is going to benefit the patient best. That has to take into account the individual, their willingness to take certain medications, for example, pills versus interferon injection. Some people have an aversion to self-injection, which we have to take that into account. What are the other medical conditions that the patient is dealing with?
And the reality is, in some cases, it’s cost because these medications, depending on a patient’s insurance, can have quite a different spread in terms of cost. Unfortunately, that is something we have to take into account.
Katherine Banwell:
Let’s talk about what sort of tests should be done following an MPN diagnosis. Can you tell me about those?
Dr. Raajit Rampal:
Yeah. Fundamental to the MPN itself, the things that we really want to know is, in most cases, a bone marrow examination is needed because that will tell us really what the disease is that we’re dealing with. It will tell us about the genetics. I strongly believe we have to be comprehensive in our genetic assessments because that does prognosticate and sometimes gives us an opportunity in terms of treatment. Chromosomal analysis. These are the basic bread and butter hematology tests we want to do from the bone marrow to really understand what the patient’s disease is.
Beyond that, I think that particularly in patients with PV and ET, it’s important that we partner with their primary care physicians to make sure that they’ve had, for example, testing for diabetes, a recent lipid profile, any cardiovascular tests, particularly measurements of blood pressure because these things are all important in terms of an ET or PV patient’s risk of having a blood clot. So, there are, again, things that are within hematology realm but then, there are other general health things that become really important in somebody who is diagnosed with PV or ET.
Katherine Banwell:
How often should lab tests of blood work be done?
Dr. Raajit Rampal:
It really depends on the patient. For some patients with PV, for example, they need to have their blood checked every three weeks because they’re having frequent phlebotomies. Whereas some patients with ET could probably go forward to six months between blood tests.
So, it depends on the individual.
Katherine Banwell:
How can results of biomarker testing affect treatment choices for patients with MPNs?
Dr. Raajit Rampal:
question. The genetics are becoming increasingly important in our treatment decisions. So, let’s take a simple example, which is patients with ET. Calreticulin and JAK2 and MPL are the three most common mutations that we see. But they have very different invocation. So, somebody could have a calreticulin-mutated ET and based on them having that calreticulin mutation and no other factors like no history of clotting, that patient may never need to go on a medication aside from aspirin. And even early on, it’s debatable whether or not some of these patients really need aspirin at all.
Whereas somebody who had a JAK-2 mutant ET, our guidelines and data suggests that that person, once they reach a certain age, should probably be on medication. So, that’s kind of perhaps one of our more clearcut examples of a genetic biomarker telling us how to approach treatment.
And then, it gets more nuanced from that and more exciting and interesting in the sense that there are mutations, for example, that occur in myelofibrosis and in patients whose disease is progressing towards leukemia, such as IDH mutations. And these are things that are now targetable with FDA-approved drugs.
And there are now clinical trials combining JAK inhibitors and IDH inhibitors for patients who have more advanced disease who have these IDH mutations. So, you go from on one end, these genomic markers being of prognostic significance and now, on the other hand, we’re getting to a point where, in some cases, they might tell us how to best treat a patient.
Katherine Banwell:
Dr. Rampal, should all patients diagnosed with MPN’s undergo molecular testing?
Dr. Raajit Rampal:
I strongly believe that. I think that we’ve learned so much that these tests have prognostic value.
And in some cases, it may suggest a slightly different diagnosis. I definitely think that should be the case.
Katherine Banwell:
What should patients be asking once they have the results?
Dr. Raajit Rampal:
What does it mean? That’s the most basic and fundamental question. It’s one thing to get a list of mutations. But the real bread and butter question is what does this mean to the disease and my prognosis and my treatment? Those are the key questions.
Katherine Banwell:
So, what are the types of treatments available for MPNs? And let’s start with myelofibrosis or MF.
Dr. Raajit Rampal:
If we had had this discussion five years ago, it would be pretty simple, and it would take a minute or two. And that’s completely changing and that’s amazing, and it’s good for all of our patients.
Right now, for patients with MF, it depends on what the issue is. If the issue is symptoms or spleen, JAK inhibitors are our first line of therapy. Three approved JAK inhibitors are currently available, two on the first side ruxolitinib (Jakafi) and fedratinib (Inrebic). And pacritinib (Vonjo) can be used for patients with really low platelet counts.
There is a fourth JAK inhibitor that we expect to be, hopefully, approved in June of this year, momelotinib. So, the landscape is about to complete broaden in terms of just JAK inhibitors.
But beyond the JAK inhibitors themselves, there are a number of late stage clinical trials that are combining JAK inhibitors with agents that work through a different mechanism that don’t work through inhibition of the JAK pathway. So far, these drugs have all shown promise in early phase trials. Now, the definitive Phase III trials are being done. We have to wait and see what the data tells us. But if these are positive trials, this could completely alter the landscape of MPN.
Katherine Banwell:
There’s also transplants available, right?
Dr. Raajit Rampal:
Correct. Transplants for more advanced patients, which comes with some major risks. And so, that has to be thought of very carefully in terms of the risks and benefit. But it is a potentially curative strategy.
Katherine Banwell:
Let’s turn to polycythemia vera or PV. What types of treatments are available?
Dr. Raajit Rampal:
It’s really quite a range. So, there are things like phlebotomy and aspirin, which has been the mainstay of therapy for many years. There are drugs like hydroxyurea (Hydrea), interferons, JAK inhibitors. So, ruxolitinib is approved in certain settings for treating polycythemia vera. So, the landscape is broad. There are a lot of questions going on right now with polycythemia vera with regards to how it should best be treated. Is the mainstay of phlebotomy and aspirin really what we should be doing or should we be giving patients treatment earlier on.
And there is some data to suggest that. There is this drug called ropeginterferon (Besremi) that’s FDA-approved for polycythemia, which was compared in the study to phlebotomy and aspirin.
And at least the data suggests that there may be better control of the disease and less progression possibly, and it’s a small number of patients, by treating patients earlier. Whereas we would have just given phlebotomy and aspirin. So, it’s something to consider. There are drugs in clinical trials as well that look promising one of which is called rusfertide, which actually works by changing the way iron is used by the body.
Iron is a key component to hemoglobin and it is, of course, a key component to polycythemia in the sense that we phlebotomize patients to make them iron deficient and that’s how we control the disease. But this is a pharmacological way to do that. So, that drug is now in Phase III trials. So, that may also alter the landscape of treatment of PV in the near future.
Katherine Banwell:
Finally, how is essential thrombocythemia treated?
Dr. Raajit Rampal:
So, in some cases, with absolutely nothing as we had talked about a moment ago. There is some thought that in really, really low-risk patients. Maybe you don’t need to do anything except observe them. Whereas most patients are on an aspirin. And beyond that, we have drugs like interferon, pegylated interferon, and hydroxyurea and anagrelide, all of which can be utilized. It’s not entirely clear if there is one distinct first line treatment that is the best but these drugs are all active. JAK inhibitors have been studied in this setting. And to date, the data hasn’t led to their approval but, certainly, people have studied it.
Katherine Banwell:
Dr. Rampal, how can you tell if a treatment is effective? Are there signs that you look for?
Dr. Raajit Rampal:
Well, I think it’s a couple of things.
One, are we meeting the treatment goals in terms of are we controlling blood counts with ET or PV? That’s one of the first principles in management. And with regards to MF, the same thing. Are patients’ symptoms being controlled? Is the spleen being adequately controlled? And then, there’s the symptom burden because just because the blood counts are being controlled, patients may still have symptoms, in which case, they are not being adequately treated. And then, we have to do our best to try to find a treatment strategy that does control their blood counts but also does control their symptoms.
So, there is the blood count perspective but there is the symptom perspective as well.
Katherine Banwell:
How do you know when it’s time to change treatments?
Dr. Raajit Rampal:
Well, I think really two things. One is if we aren’t meeting our goals like we just talked about. But the other aspect of that is if we are incurring toxicities that are just not tolerable to the patient and that’s a reason to change therapy always.
Katherine Banwell:
Many patients, of course, worry about disease progression. Are there key predictors or tests for progression that patients should know about?
Dr. Raajit Rampal:
This is a key area of investigation currently. I think one of the things that patients say to us so often when we meet them is what’s going to happen to me. And right now, we don’t have great prediction tools. We can say on a population level well, there is X percent of chance of progression at 15 years. That’s useful if you’re talking about a population. That’s not really useful if you’re talking to an individual. Because if I say to somebody there’s a 20 percent chance of your disease progressing to leukemia, it doesn’t really make a difference. That’s a meaningless statement because if you’re in the 20 percent who progress, it’s not a relevant statistic anymore.
It’s sort of a binary thing. We’ve got to do better at developing this. This is something that the MPN Research Foundation is really heavily invested in in trying to identify predictive biomarkers.
If we can do that, then perhaps what we can do is say to a patient this is really what we think your actual risk is. And then, the next step is asking the question if we intervene early, can we prevent that progression from occurring. So, that’s where I think we need to go. We aren’t there yet.
Katherine Banwell:
What signs or symptoms do you look for that may indicate that the disease is progressing?
Dr. Raajit Rampal:
The blood counts are often the canary in the coal mine regardless of the disease. They can tell us if ET or PV is progressing into MF or whether MF is progressing to more of a leukemic phase. Changes in symptoms sometimes can be a harbinger of disease progression. So, Patient 2, for example, is doing really well and now, he’s having drenching sweats and losing weight. So, those types of symptoms are a sign that physical findings is the size of the spleen if it’s increasing.
All of those things together give us a hint about progression.
Katherine Banwell:
Well, is there any way to prevent progression?
Dr. Raajit Rampal:
That is the million dollar question. Again, that’s where we ultimately need to be. We want to be able to intervene to a point where patients don’t get that sick. It would be amazing if we’d come to the point where we can intervene early and nobody progresses to late stage MF. Nobody gets leukemia. And I think that’s a worthy goal. That’s not something that we should think is too lofty of a goal. That should be our ultimate goal here. And a number of groups are investigating this exact question. It’s complicated and it’s going to take time. But I think that’s a worthwhile investment.
Katherine Banwell:
Let’s talk about MPN symptoms and treatment side effects. Here’s a question we received from a viewer before the program. How common is peripheral neuropathy in primary myelofibrosis?
And what is the best treatment for it?
Dr. Raajit Rampal:
Well, by itself, it’s not a very common symptom of MF by itself. Can it be a symptom? Sure. But there are also a number of things that can cause peripheral neuropathy. So, I’m not sure there’s a best treatment.
But what needs to be done is a thorough investigation. There can be a number of causes. It could be nerve injury. It could be a deficiency in vitamins like B12. There are a lot of things that could cause it. So, that type of a symptom needs to be thought of in a broad way in terms of diagnosis.
Katherine Banwell:
Jeff sent in this question. How could I manage the itching? Are there new treatments or strategies to live with itching?
Dr. Raajit Rampal:
Very common thing. And it’s an interesting thing explaining to when we teach our trainees about this symptom, we have to impress on them the fact that itching is not the itching that everybody else experiences.
This is a very profoundly different symptom. It’s debilitating for so many people. I have patients who go to the Emergency Room for that. That’s how terrible it could be. There are a lot of things that could be tried. JAK inhibitors, in my experience, work very well for itching but not in everybody. We use sometimes antihistamines that can work well. Sometimes, antidepressants can work well, not because they’re treating depression but because of other properties that they have. And sometimes, UV light therapy can be useful tool here, too. A lot of patients swear by it.
Katherine Banwell:
Another common side effect is fatigue. Do you have any advice for managing this symptom?
Dr. Raajit Rampal:
Fatigue is the most common symptom across MPNs. And it is also one of the most difficult things to treat. Part of the issue is trying to figure out what does fatigue mean to the patient.
When someone says they’re tired, does that mean they’re sleeping all of the time? Does that mean they don’t have get up and go? The first step is always understanding what does fatigue mean to the patient? And then, the second is trying to dissect that. In some cases, it’s related to anemia, in some cases, it’s not related to anemia and it’s just the disease itself.
And in some cases, you have to think outside of the box about general medical issues like thyroid dysfunction that could be at play here. So, there isn’t one best fit.
But the first test is always to dig deep. When someone says they have fatigue to dig deeper and try to figure out what is that really.
Katherine Banwell:
What other common symptoms do you hear about from patients? And what can be done about those?
Dr. Raajit Rampal:
There are a lot of different things. It’s a spectrum. So, I think that itching and fatigue are very common. Feeling full early is, that’s a big thing, particularly in myelofibrosis patients.
Bone pain, that’s another big one, particularly in myelofibrosis. There is not one therapy that is best for all. I think the JAK inhibitors, certainly, benefit many of these symptoms. But they don’t benefit everybody and not to the extent that makes it tolerable for everybody. So, often times, we struggle with this and try a lot of different things. But, again, I think one of the things to always remember is we don’t always want to say that this must be because of the MPN. Sometimes, symptom is arising because of another medical condition that’s going on concurrently.
Katherine Banwell:
That’s good advice. Thank you. Let’s answer a few more audience questions we received. This one is from Calvin, “If your hematologist says you’re stable and responding well to Hydrea, should you still seek out a second opinion?”
Dr. Raajit Rampal:
It’s never wrong to seek out a second opinion. I strongly believe that, especially when you’re dealing with a disease that’s rare like this.
And even seeking out a second opinion, even if you’re under the care of an expert in the field is never a wrong thing. I think that no one person knows everything. And sometimes, people’s experience and perspective is different. So, I don’t think that’s a bad thing ever.
Katherine Banwell:
As a follow-up to Calvin’s question, is it sufficient to just look at what the blood tests reveal? Or does having bone marrow biopsy dictate what treatment you should follow?
Dr. Raajit Rampal:
I think the bone marrow is important, particularly at initial diagnosis or when there is a change. The blood counts are the canary in the coal mine. So, they tell us is there something else going on that we’re not thinking about. And that’s when the bone marrow becomes important. So, I definitely think bone marrow is important at certain points in the disease.
Katherine Banwell:
Sandra has this question, “Are there new treatments for polycythemia vera being researched beyond interferon?”
Dr. Raajit Rampal:
Yeah. So, we talked about rusfertide as an example of this. And there are, certainly, other drugs that have been evaluated in this space. So, there is a lot of work going on for this disease, which is really encouraging.
Katherine Banwell:
Carolyn sent in this question, “Is there a possibility of bone marrow fibrosis reversal in myelofibrosis without a stem cell transplant?”
Dr. Raajit Rampal:
The answer is yes. So, even with JAK inhibitors, we see that about a third of patients will have a reduction in bone marrow fibrosis. And this is a key question being investigated with some of the newer therapies that are being introduced into the treatment of myelofibrosis. And, certainly, we’ve seen data to date that suggests that the fibrosis can be reduced if not potentially eliminated in some cases.
Katherine Banwell:
Dr. Rampal, should all patients diagnosed with MPNs undergo molecular testing?
Dr. Raajit Rampal:
I strongly believe that. I think that we’ve learned so much that these tests are prognostic value.
And in some cases, it may suggest a slightly different diagnosis. I definitely think that should be the case.
Katherine Banwell:
What should patients be asking once they have the results?
Dr. Raajit Rampal:
What does it mean? That’s the most basic and fundamental question. It’s one thing to get a list of mutations. But the real bread and butter question is what does this mean to the disease and my prognosis and my treatment? Those are the key questions.
Katherine Banwell:
Andrew wants to know does Jakafi cause other mutations to develop?
Dr. Raajit Rampal:
That’s a really good question. Right now, we don’t think the answer is necessarily yes. We have seen that in some patients where the disease has progressed on Jakafi, mutations have emerged.
But the problem is that genetic testing has limits of detection. In other words, the mutation appears, it may not have just appeared or been caused by the drug but that it may have been below our limits of detection and actually grew while the patient was on therapy, which does not mean that the drug caused the mutation but that it was allowed to emerge during treatment with the specific drug. So, that is an area of investigation.
Katherine Banwell:
Well, thank you, Dr. Rampal. And please continue to send in your questions to question@powerfulpatients.org and we’ll work to get them answered on future webinars.
You mentioned earlier clinical trials. And I’d like to dig a little bit deeper. Where do these fit into the treatment plan?
Dr. Raajit Rampal:
I think they should always be considered. None of the therapies that we have do we consider curative. And in many cases, standard therapy is fine given a patient’s clinical situation. In a case where standard therapy is not working or where we think that a patient’s prognosis is particularly challenging, or if they have mutations that may confer resistance to current therapies.
I think in those scenarios, a trial should always be considered.
Katherine Banwell:
So, if a patient is interested in possibly participating in a clinical trial, what kinds of questions should they be asking their healthcare team?
Dr. Raajit Rampal:
All of these trials are different. I think the first thing is to discuss what’s the risk, what’s the benefit of any given trial or drug. What stage and development is it? What’s the evidence to support it? And what can I expect from it?
Katherine Banwell:
What about cost?
Dr. Raajit Rampal:
So, trials, in general, have two components. One is what we call standard of care meaning that things we would do normally for in the course of a patient’s treatment would be billed to a patient’s insurance as if they weren’t on a trial.
Almost all trials, the study drug or any tests that are being done specifically with regards to the study drug are all covered by whoever is sponsoring the trial.
Katherine Banwell:
How do patients find out about where the clinical trials are taking place?
Dr. Raajit Rampal:
Usually, their physician should either, if they’re in a specialized center, they’ll have access there. But if they’re interested in trials and they’re being seen, for example, by a physician in the community who doesn’t necessarily specialize, asking for a referral to a major center where that MPN expertise is not an unreasonable approach to that. There is also clinicaltrials.gov where patients can go look for ongoing trials for their particular diagnosis.
Katherine Banwell:
So, if patients want to learn more about MPNs, what sort of resources would you recommend?
Dr. Raajit Rampal:
The thing I always say to patients is the internet is a very dangerous place for a variety of reasons. We have to, I think, do a good job of communicating to patients what are the resources. And the ones that I always point patients to are, for example, the MPN Advocacy International, the MPN Research Foundation, The Leukemia & Lymphoma Society, and the American Cancer Society. Those are sources of information that are vetted by physicians.
Some of that information is specifically for patients. Those, to me, are good sources for patients to read.
Katherine Banwell:
Dr. Rampal, as we close out our conversation, I wanted to get your thoughts on where we stand with progress and MPN care. Are there advances in research and treatment that make you hopeful?
Dr. Raajit Rampal:
Without a doubt. I think I’ve seen more progress in the last three years than I’ve seen in the last 10 years. And we have so many new drugs coming forward, new questions that we’re trying to answer, tough questions as you alluded to. The question about prognosis but also intervening early to prevent progression of disease. These are things that are difficult questions that we are trying to dig into now. So, I think we should be optimistic. We are seeing so many excellent developments. We’ll have to see how far they’re going to take us. I don’t think we know the answer to that. But this is an exciting time.
Katherine Banwell:
Dr. Rampal, thank you so much for joining us.
Dr. Raajit Rampal:
My pleasure.
Katherine Banwell:
And thank you to all of our partners. To learn more about MPNs and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for being with us today.
Finding an MPN Treatment Approach That Is Right for You
Finding an MPN Treatment Approach That Is Right for You from Patient Empowerment Network on Vimeo.
Appropriate and effective treatment is an essential part of thriving with an MPN. Dr. Joseph Scandura reviews the goals of MPN treatment and factors that should be considered when choosing a therapy.
Dr. Joseph Scandura is an Associate Professor of Medicine and Scientific Director of the Silver MPN Center at Weill Cornell Medicine. Learn more about Dr. Scandura.
Related Programs:
How Should You Participate in MPN Care and Treatment Decisions? |
Transcript:
Katherine Banwell:
One part of thriving with an MPN is finding a treatment approach that manages your disease, the symptoms of your MPN, and that fits with your lifestyle. So, what are the factors that are considered when choosing treatment for patients with ET, PV, and MF?
Dr. Scandura:
Certainly, the goals of the therapy. So, is the therapy one that I would be looking to maybe delay progression or for long-term potential benefits, or is it something I need now to control short-term risks such as blood clots? The goals of the patient because some therapies may be more suitable to the goals of one patient than another.
And the other – you know, there’s clinical features that may kind of push towards one approach versus another. Certainly, in a 20-year-old patient, I’m thinking about fertility. I’m thinking about a normal life expectancy. In a 90-year-old patient, I have a different set of concerns, multiple medications – what am I going to do that might be affecting their other comorbid conditions?
Katherine:
Right. Right.
Dr. Scandura:
I think about what are my near-term and long-term goals? So, obviously, age becomes a factor there. If I’m 95 years old, no matter what I do that person is not going to live 20 years. If that person’s 20 years old and they’re not living 30, 40, 50, 60 years, that’s a real shame. That’s a huge loss of life. So, that helps kind of point me in one direction or another.
And, then, there’s different types of therapy. There are injectable agents. There are pills. There are drugs that have been used for a long time but don’t really have an FDA approval. There are drugs that are approved for certain indications.
And, as physicians, we can sometimes stretch that based upon clinical judgment. So, I think a lot of that goes into the discussion I have with patients about therapy.
And that’s always – you know, I present to them what the options are, what I think the benefits might be, what the potential toxicities are, and then we discuss.
How Are ET, PV and Myelofibrosis Monitored?
How Are ET, PV and Myelofibrosis Monitored? from Patient Empowerment Network on Vimeo.
MPN specialist and researcher Dr. Joseph Scandura reviews tools that are used to monitor patients with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), including routine blood work and symptom management
Dr. Joseph Scandura is an Associate Professor of Medicine and Scientific Director of the Silver MPN Center at Weill Cornell Medicine. Learn more about Dr. Scandura.
Related Programs:
Transcript:
Katherine Banwell:
I would imagine monitoring patients is different for each of the MPNs. So, how are patients typically monitored over time, and let’s start with essential thrombocythemia?
Dr. Scandura:
Yeah. I think – again, it’s similar. You know, what’s near-term, what’s long-term? And so, in all of these diseases, thrombosis risk is a near-term risk. That’s something that I am monitoring in certain ways to help mitigate that risk. In ET and PV, I approach them similarly. Blood counts are certainly – these are diseases of the blood forming system. Certainly, monitoring blood counts I find helpful. But the reality of it is, in ET, there is not a clear linkage between blood counts and risks.
And so, I like to keep the platelet count near normal if I can. But I also recognize that it may not be worth suppressing all of the blood counts to achieve that landmark, because it’s not clear that that’s really reducing the risk any more than just having somebody on a medication that helps control the blood counts. In polycythemia vera, different blood counts are very important. The red blood cells are kind of like part of the clotting risk. We know from clinical trials that keeping the red blood cell parameters within certain ranges reduces the risk of clotting. And so, what I monitor in polycythemia vera is the hematocrit. In women, I like to keep it below 42. In men, I like to keep it below 45.
But I don’t just – I’m not a slave to the hematocrit. I am keeping an eye on the other blood counts and the other red blood cell parameters. So, for instance, what’s the size of the red blood cells? That tells me a little bit about what’s going on in the blood formation for that patient. And what’s the number of red blood cells? So, sometimes people can have very small red cells, because they’re a little iron-deficient and have a huge surplus of the number of red blood cells. And that tells me a little bit about how their blood forming system is responding to therapy.
Iron deficiency in polycythemia vera is very prominent. I personally believe it’s a very major driver of symptoms in patients who are receiving phlebotomy as part of their care. And it’s something that I monitor and really counsel patients on. My goal is to make phlebotomy independent, but it can take a while.
Everybody starts out iron-deficient, and then we take iron out of their body through blood with the phlebotomy. And that makes them more iron-deficient.
Katherine:
Right.
Dr. Scandura:
I monitor symptoms from patients, and sometimes that can tell me that their disease needs to be – their treatment needs to be tweaked a little bit, even something as simple as aspirin. People can sometimes have burning in the skin or itching that is sometimes responsive to changing the aspirin dose or how it’s given, once a day versus twice a day.
And that simple thing can be a big change for a patient who’s kind of, literally, climbing out of their skin or wishing they could and to try and find something that is helping.
I had a patient the other day. He had COVID. I said, “Oh, you should probably get this medication.” Do you have your primary care physician? Who’s taking care of you?” And he goes, “Well, to be honest with you, you’re my guy.” And so, it’s true. I see this patient a lot. And so, sometimes they forget. If I’m not paying attention to their blood pressure, the risks or treatment of diabetes, cholesterol, lipids, their screening programs for mammogram or colonoscopy, health maintenance issues, I do keep an eye on that in patients, because I do think it’s a part of the MPNs.
I think that there are excess risks for patients for some of these factors. Certainly, if you think of it as three strikes, they get a strike for having an MPN. I don’t want them to have any other strikes. So, diabetes, hypertension, those are strikes that I can potentially, at least, treat or refer them to somebody to help comanage with me. And so, that’s kind of my general approach.
Katherine:
What about patients who have myelofibrosis? Are they monitored more closely?
Dr. Scandura:
Yeah, I think it depends a little bit on the patient. Patients with early myelofibrosis often don’t have any symptoms or near-term risks much different than those from ET or PV. As the disease can progress, then some of these patients have more profound problems with symptoms, which I may be trying to find a solution to make them feel better. And also, blood counts can become more of an issue.
Transfusions in some patients who are very high white blood cell count, the spleen is often quite enlarged. Although, in my experience, most patients aren’t really bothered by the size of their spleen as the physicians are. But it is something where I think, on average, they’re monitored a little bit more closely to quite a bit more closely depending on the patient.
Katherine:
What happens if someone suddenly has a change in blood counts? What do you do?
Dr. Scandura:
Yeah. I mean, repeat it. That’s the first thing. Also, check what’s going on. It’s not uncommon in patients with MPNs that I’ll see them and the counts are a little bit out of whack, the white count is much higher than it’s been, and questioning them. “Oh, yeah. I had X, Y, or Z last week or the week before.” It used to be a upper respiratory tract infection, or they had a minor surgical procedure.
And sometimes the responses to these things can be accentuated in patients with MPNs. And so, if that’s what of this story, I certainly would repeat it and let things calm down a little. And that’s often all it is. I’m much more of a monitor of the trends. So, one-time measure doesn’t generally excite me. It might make me want to have a follow-up a little more – in a shorter period of time. Of course, it depends on what the change is. But, for most of the changes that we observe, they’re relatively minor. And I will monitor them over time.
If I see a trend where something is progressively increasing or decreasing over time, then I start thinking about what else is going on. And that’s always in the context of what’s going on with the patient. How are they feeling? What’s their physical exam like? What are the other laboratory values like?
Katherine:
When is a bone marrow biopsy necessary?
Dr. Scandura:
I would say a bone marrow biopsy is absolutely necessary at the time of diagnosis. I personally do not routinely monitor by bone marrow biopsy unless it’s part of a clinical trial.
But I do perform a bone marrow or want to look at the bone marrow morphology if there is one of these changes or at least a trend that I want a little bit more information about. And so, if – or if it’s been a very long time since somebody has had a bone marrow. If it’s been five or ten years, then sometimes I may recommend we look just so we can collect a little bit more up-to-date information.
But I don’t routinely do a bone marrow, but I will do it if there are laboratories that are kind of trending in the wrong direction, there’s symptoms, there’s physical findings that I’m just not sure about. And I think it would help me be more sure as to what’s going on and be able to discuss that with the patient. Sometimes, just to say, “Hey. Look, we were worried about this, but the bone marrow looks really good.”